Compositions for delivering hypnotic agents across the oral mucosa and methods of use thereof

ABSTRACT

The present invention provides novel compositions for the delivery of a hypnotic agent across the oral mucosa. In particular, the buffer system in the compositions of the present invention raises the pH of saliva to a pH greater than about 7.8, thereby facilitating the substantially complete conversion of the hypnotic agent from its ionized to its un-ionized form. As a result, the dose of hypnotic agent is rapidly and efficiently absorbed by the oral mucosa with surprisingly low inter-subject variability. Furthermore, delivery of the hypnotic agent across the oral mucosa advantageously bypasses hepatic first pass metabolism of the drug and avoids enzymatic degradation of the drug within the gastrointestinal tract. Methods for using the compositions of the present inversion for treating sleep disorders such as insomnia are also provided.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/253,241, filed Apr. 15, 2014, which is continuation of U.S.application Ser. No. 13/360,533, filed Jan. 27, 2012, which is acontinuation of U.S. application Ser. No. 12/722,398, filed Mar. 11,2010, which a continuation of U.S. application Ser. No. 11/833,323,filed Aug. 3, 2007, now issued as U.S. Pat. No. 7,682,628, which is acontinuation of U.S. application Ser. No. 11/060,641, filed Feb. 16,2005, now issued as U.S. Pat. No. 7,658,945, which claims priority toU.S. Provisional Application No. 60/598,629, filed Aug. 3, 2004 and U.S.Provisional Application No. 60/608,957, filed Feb. 17, 2004, which wasconverted from U.S. application Ser. No. 10/783,118. All of theabove-referenced applications are herein expressly incorporated byreference in their entirety for all purposes.

BACKGROUND OF THE INVENTION

Insomnia is a condition that affects a person's ability to fall asleepor to maintain sleep. It is the most common sleep disorder, affectingmillions of Americans each year. Benzodiazepines, which are available asshort, intermediate, or long-acting hypnotic agents, have proven usefulin treating insomnia. These benzodiazepines are thought to bindnon-selectively to benzodiazepine₁ (omega₁) and benzodiazepine₂ (omega₂)receptors. This non-selective binding may be responsible for some of thepotential problems associated with the use of benzodiazepine compoundsas hypnotics. For example, some benzodiazepines are thought to interferewith memory, cognition, and psychomotor function. In addition, problemswith altered sleep architecture, rebound insomnia, hangover effects, andabuse potential have been reported with benzodiazepine use.

Selective benzodiazepine₁ receptor agonists have been developed andstudied. For example, zolpidem (Ambien®; Searle and Co.) and zaleplon(Sonata®; Wyeth-Ayerst Co.) are non-benzodiazepine sedative agentsthought to selectively bind to benzodiazepine (BZ₁) receptors. Zolpidem,an imidazopyridine, has been demonstrated to reduce sleep latency,increase sleep duration, and reduce nighttime awakenings. In addition,zolpidem has been found to preserve stage III and stage IV sleep, and toresult in less disruption of REM (Rapid Eye Movement) sleep. Zaleplon isa pyrazolopyrimidine derivative, which has also proven useful as ahypnotic agent. However, zolpidem and zaleplon are both poorly solublein aqueous media.

Typically, these hypnotic agents are delivered as oral dosages, whichare formulated, for example, as tablets or capsules that are swallowed.Oral administration, however, has several disadvantages, such as druglosses during hepatic first pass metabolism, during enzymaticdegradation within the GI tract, and during absorption. These druglosses not only increase the variability in drug response, but alsooften require that the medicament be given in greater initial doses. Inaddition, because the drug has to pass through the gastrointestinalsystem in order to enter the blood stream, the time to reach atherapeutic effect may be quite long, typically around forty-fiveminutes or longer.

Accordingly, other routes of drug administration have been investigated,including those involving transport across the mucous membranes. Of thevarious mucous membranes (e.g., oral, rectal vaginal, ocular, nasal,etc.), drug delivery via the mucous membranes in the oral cavity seemsto be the most easily tolerated by patients. In addition to avoiding theproblems with traditional oral administration, drug delivery via themucous membranes of the oral cavity has certain other advantages, due tothe properties of the oral mucosa itself. For example, the mucousmembranes of the oral cavity are highly vascularized and well suppliedwith lymphatic drainage sites.

In general, the mucous membranes of the oral cavity can be divided intofive main regions: the floor of the mouth (sublingual), the cheeks(buccal), the gums (gingival), the roof of the month (palatal), and thelining of the lips. These regions differ from each other with respect totheir anatomy, drug permeability, and physiological response to drugs.For example, in terms of permeability, sublingual is more permeable thanbuccal, which is more permeable than palatal. This permeability isgenerally based on the relative thickness and degree of keratinizationof these membranes, with the sublingual mucosa being relatively thin andnon-keratinized, the buccal mucosa being thicker and non-keratinized,and the palatal mucosa being intermediate in thickness, but keratinized.

In addition to the differences in permeability of the various mucousmembranes, the extent of drug delivery is also affected by theproperties of the drug to be delivered. The ability of a molecule topass through any mucous membrane is dependent upon its size, its lipidsolubility, and the extent to which it is ionized, among other factors.

The extent to which a drug is ionized has further been investigated withrespect to drug delivery across the mucous membranes. Ionization isdependent on the dissociation constant (pKa), and the pH of themolecule's surrounding environment. In its un-ionized form, a drug issufficiently lipophilic to traverse a membrane via passive diffusion. Infact, according to the pH partition hypothesis, only un-ionized,non-polar drugs will penetrate a lipid membrane.

At equilibrium, the concentrations of the un-ionized form of the drugare equal on both sides of the membrane. As the concentration gradientdrives passive diffusion, an increase in the percentage of theun-ionized form of a drug correspondingly increases the transmucosalabsorption of the drug. Maximum absorption across the membrane isthought to occur when a drug is 100% in its un-ionized form. Similarly,absorption across the membrane decreases as the extent of ionizationincreases. Therefore, one may influence the extent of drug absorptionacross the mucous membranes of the oral cavity by altering the salivarypH.

Some of the known transmucosal dosage forms include the use of a singlebuffering agent in order to change the pH of the saliva and tissuessurrounding the buccal mucosa. However, these single buffering agentstypically react with an acid or a base to create a final pH that isdependent upon the initial pH of the saliva of the user. A bufferingagent used to attain a final pH that is dependent upon the initial pH ofthe user results in great variability. The extent of ionization, andhence the extent of absorption across the mucous membranes cannot bepredicted with any sort of accuracy. This may pose significant problemswhen calculating precise doses, minimizing variability in patientresponse, and proving consistency in drug loading to the regulatoryauthorities. In addition, a single buffering agent is typically notcapable of sustaining a given pH over a period of time for optimalabsorption. While others in the art have disclosed the use of more thanone buffering agent, these aforementioned problems are not easily curedby the nonchalant addition of an extra buffering agent, which may beunsafe and cause irreversible damage to the mucous membranes of the oralcavity. As such, a buffering system capable of achieving and sustaininga final pH independent of the initial pH in order to increasetransmucosal absorption has not heretofore been demonstrated.

Similarly, a buffer system that facilitates substantially completeconversion of the ionized form of a drug to the un-ionized form in theshortest period of time, which is critical for producing rapid deliveryof practically an entire drug dose across the oral mucosa, has notheretofore been demonstrated. Previous dosage forms resulted in greatvariability in drug delivery, due to the variability in the rates inwhich a drug was released from its carrier. That is, the rates of drugrelease in previously described chewing gums or lozenges are largelydependent upon the rate of chewing or sucking of the user. Thevariability in these rates from user to user further exacerbates theability to predict the final amount of drug that will enter systemiccirculation. In addition, the rate of drug release from the carrier isfurther dependent upon the ability of the drug to be released therefrom.Often times, the carrier (e.g., gum base) strongly adheres to the drug,making portions of the drug unavailable for absorption.

Accordingly, there is a need in the art for compositions for deliveringhypnotic agents across the oral mucosa having buffer systems thatfacilitate absorption of the agents in a safe and stable manner.Similarly, there is a need in the art for compositions for deliveringhypnotic agents across the oral mucosa having a buffer system thatproduces a final pH, independent of the initial pH, and sustains thatfinal pH for a given period of time. In addition, there is a need in theart for compositions capable of rapidly facilitating substantiallycomplete conversion of the hypnotic agent from its ionized to itsun-ionized form. The present invention satisfies these and other needs.

BRIEF SUMMARY OF THE INVENTION

The present invention provides novel compositions for the delivery of ahypnotic agent across the oral mucosa. In particular, the buffer systemin the compositions of the present invention raises the pH of saliva toa pH greater than about 7.8, thereby facilitating the substantiallycomplete conversion of the hypnotic agent from its ionized to itsun-ionized form. As a result, the dose of hypnotic agent is rapidly andefficiently absorbed by the oral mucosa with surprisingly lowinter-subject variability (e.g., lower variability than absorptionacross the gut in the same patients). Furthermore, delivery of thehypnotic agent across the oral mucosa advantageously bypasses hepaticfirst pass metabolism of the drug and avoids enzymatic degradation ofthe drug within the gastrointestinal tract. Methods for using thecompositions of the present invention for treating sleep disorders suchas insomnia are also provided.

As such, in one aspect, the present invention provides a solidcomposition for delivery of a hypnotic agent across the oral mucosa, thecomposition comprising:

-   -   (a) a hypnotic agent selected from the group consisting of an        imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine,        and a pharmaceutically acceptable salt thereof;    -   (b) a carrier that provides complete buccal or sublingual        disintegration in about 5 minutes or less following        administration to the mouth; and    -   (c) a binary buffer system comprising a carbonate salt and a        bicarbonate salt, wherein the binary buffer system raises the pH        of saliva to a pH greater than about 7.8, irrespective of the        starting pH of saliva.

In another aspect, the present invention provides a composition fordelivery of a hypnotic agent across the oral mucosa, the compositioncomprising:

-   -   (a) a hypnotic agent selected from the group consisting of an        imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine,        and a pharmaceutically acceptable salt thereof;    -   (b) a carrier; and    -   (c) a binary buffer system comprising a carbonate salt and a        bicarbonate salt,        wherein the binary buffer system raises the pH of saliva to a pH        greater than about 7.8, irrespective of the starting pH of        saliva.

In yet another aspect, the present invention provides a composition fordelivery of a hypnotic agent across the oral mucosa, the compositioncomprising:

-   -   (a) a hypnotic agent selected from the group consisting of an        imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine,        and a pharmaceutically acceptable salt thereof;    -   (b) a carrier; and    -   (c) a binary buffer system comprising a carbonate salt or a        bicarbonate salt and a second buffering agent,        wherein the binary buffer system raises the pH of saliva to a pH        greater than about 7.8, irrespective of the starting pH of        saliva.

In still yet another aspect, the present invention provides acomposition for delivery of a hypnotic agent across the oral mucosa, thecomposition comprising:

-   -   (a) a hypnotic agent selected from the group consisting of an        imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine,        and a pharmaceutically acceptable salt thereof;    -   (b) a carrier; and    -   (c) a binary buffer system comprising a metal oxide and a        citrate, phosphate, or borate salt,    -   wherein the binary buffer system raises the pH of saliva to a pH        greater than about 7.8, irrespective of the starting pH of        saliva.

In a further aspect, the present invention provides a composition fordelivery of a hypnotic agent across the oral mucosa, the compositioncomprising:

-   -   (a) a hypnotic agent selected from the group consisting of an        imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine,        and a pharmaceutically acceptable salt thereof;    -   (b) a carrier; and    -   (c) a ternary buffer system comprising a carbonate salt, a        bicarbonate salt, and a third buffering agent,        wherein the ternary buffer system raises the pH of saliva to a        pH greater than about 7.8, irrespective of the starting pH of        saliva.

In another aspect, the present invention provides a composition fordelivery of a hypnotic agent across the oral mucosa, the compositioncomprising:

-   -   (a) a hypnotic agent selected from the group consisting of an        imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine,        and a pharmaceutically acceptable salt thereof;    -   (b) a carrier; and    -   (c) a buffer system comprising a carbonate salt or a bicarbonate        salt and two or more buffering agents selected from the group        consisting of a metal oxide, a citrate salt, a phosphate salt,        and a borate salt,        wherein the buffer system raises the pH of saliva to a pH        greater than about 7.8, irrespective of the starting pH of        saliva.

In yet another aspect, the present invention provides a method fortreating a sleep disorder in a subject in need thereof, the methodcomprising:

administering to the subject a composition comprising a therapeuticallyeffective amount of a hypnotic agent selected from the group consistingof an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine,and a pharmaceutically acceptable salt thereof; a carrier; and a binarybuffer system comprising a carbonate salt and a bicarbonate salt,wherein the binary buffer system raises the pH of saliva to a pH greaterthan about 7.8, irrespective of the starting pH of saliva.

Other objects, features, and advantages of the present invention will beapparent to one of skill in the art from the following detaileddescription and figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar chart illustrating the relationship between the pH andmembrane permeation for zolpidem tartrate.

FIG. 2 shows the mean dissolution profiles for a zolpidemquick-dissolving tablet and zolpidem lozenge of the present invention.

FIG. 3 shows the plasma concentration over time in each subject forFormulation A (zolpidem sublingual powdered tablet) at a 2 minuteswallowing time.

FIG. 4 shows the plasma concentration over time in each subject forFormulation A at a 5 minute swallowing time.

FIG. 5 shows the plasma concentration over time in each subject forFormulation A at a 10 minute swallowing time.

FIG. 6 shows the mean plasma concentration over time for Formulation Aat the 3 different swallowing times and for Formulation B (PO Ambien®),which was obtained from the literature.

FIG. 7 shows the mean plasma concentration over time for Formulation Aat swallowing times of 2 and 5 minutes using the data from all subjectsor excluding the data from subjects 3, 6, and 7.

FIG. 8 is an expanded view of the first 90 minutes shown in FIG. 4.

FIG. 9 shows a representative plasma concentration over time forFormulation C (SL Tablet) at swallowing times of 2 and 5 minutes and forFormulation B.

FIG. 10 shows a representative plasma concentration over time forFormulation D (FS Tablet) at swallowing times of 2 and 5 minutes and forFormulation B.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

As used herein, the following terms have the meanings ascribed to themunless specified otherwise.

The term “sleep disorder” refers to a disruptive pattern of sleeparising from many causes including, without limitation, dysfunctionalsleep mechanisms, abnormalities in physiological functions during sleep,abnormalities of the biological clock, and sleep disturbances that areinduced by factors extrinsic to the sleep process. In particular, theterm encompasses disorders associated with difficulties in stayingasleep and/or falling asleep such as insomnia (e.g., transient,short-term, and chronic), delayed sleep phase syndrome,hypnotic-dependent sleep disorder, and stimulant-dependent sleepdisorder; disorders associated with difficulties in staying awake suchas sleep apnea, narcolepsy, restless leg syndrome, obstructive sleepapnea, central sleep apnea, idiopathic hypersomnia, respiratory muscleweakness-associated sleep disorder; disorders associated withdifficulties in adhering to a regular sleep schedule such as sleep statemisperception, shift work sleep disorder, chronic time zone changesyndrome, and irregular sleep-wake syndrome; disorders associated withabnormal behaviors such as sleep terror disorder (i.e., parasomnia) andsleepwalking (i.e., somnambulism); and other disorders such as sleepbruxism, fibromyalgia, aud nightmares.

The term “insomnia” refers to a sleep disorder characterized by symptomsincluding, without limitation, difficulty in falling asleep, difficultyin staying asleep, intermittent wakefulness, and/or waking up too early.The term also encompasses daytime symptoms such as sleepiness, anxiety,impaired concentration, impaired memory, and irritability. Types ofinsomnia suitable for treatment with the compositions of the presentinvention include, without limitation, transient, short-term, andchronic insomnia. The term “transient insomma” refers to insomnialasting for a few nights. The term “short-term insomnia” refers toinsomnia lasting for about two to about four weeks. The term “chronicinsomnia” refers to insomnia lasting for at least one month.

The terms “therapeutic agent” and “drug” are used interchangeably hereinto refer to a substance having a pharmaceutical, pharmacological,psychosomatic, or therapeutic effect. Preferably, the therapeutic agentor drug is a hypnotic agent. Suitable hypnotic agents for use in thepresent invention include, without limitation, an imidazopyridinecompound such as zolpidem or alpidem; a dihydropyrrolopyrazine compoundsuch as zopeclon; a pyrazolopyrimidine compound such as zaleplon orindiplon; pharmaceutically acceptable salts thereof; and combinationsthereof. In a particularly preferred embodiment, the hypnotic agent iszolpidem, in all suitable forms.

The term “therapeutically effective amount” refers to the amount of ahypnotic agent that is capable of achieving a therapeutic effect in asubject in need thereof. For example, a therapeutically effective amountof a hypnotic agent can be the amount that is capable of preventing orrelieving one or more symptoms associated with a sleep disorder.

The term “bioavailability” refers to the rate and/or extent to which adrug is absorbed or becomes available to the treatment site in the body.

The terms “disintegration” and “dissolution” are used interchangeablyherein to refer to the reduction of a solid dosage form of the presentinvention to a liquid form. More particularly, a complete disintegrationor dissolution of a solid dosage form refers to less than about 25% byweight of the solid dosage form remaining in the mouth following anappropriate time period, e.g., 5 minutes or less, after administration.Suitable methods known in the art for determining the disintegrationprofile of a solid dosage form inclnde, e.g., the United StatesPharmacopeia (USP) disintegration test. Suitable methods known in theart for determining the dissolution profile of a solid dosage forminclude, e.g., USP dissolution tests such as USP <711> Apparatus 1 orUSP <711> Apparatus 2.

As used herein, the phrase “substantially complete conversion of thehypnotic agent from its ionized to its un-ionized form” refers togreater than about 50% conversion of the hypnotic agent from its ionizedform into its un-ionized form. For example, the buffer system may favorat least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%conversion of the hypnotic agent from its ionized form into itsun-ionized form. In some embodiments, the conversion occurs within about10 minutes following administration.

The term “variability” refers to inter-subject variability in terms ofthe percent of relative standard deviation (RSD) for the maximum plasmaconcentration (C_(max)) and the time to reach the maximum plasmaconcentration (T_(max)). Notably, the compositions of the presentinvention have an RSD for C_(max) of about 27% versus about 45% forcommercial oral tablets such as Ambien® tablets. Further, thecompositions of the present invention have an RSD for T_(max) of about50% versus about 100% for commercial oral tablets such as Ambien®tablets.

The term “administering” refers to administration of the compositions ofthe present invention to the mucous membranes of the oral cavity (i.e.,oral mucosa). Examples of suitable sites of administration within theoral mucosa include, without limitation, the mucous membranes of thefloor of the mouth (sublingual mucosa), the cheeks (buccal mucosa), thegums (gingival mucosa), the roof of the mouth (palatal mucosa), thelining of the lips, and combinations thereof. Preferably, thecompositions of the present invention are administered to the sublingualmucosa, buccal mucosa, or a combination thereof.

II. General

The present invention provides novel compositions for the delivery of ahypnotic agent across the oral mucosa. In particular, the buffer systemin the compositions of the present invention raises the pH of saliva toa pH greater than about 7.8, thereby facilitating the substantiallycomplete conversion of the hypnotic agent from its ionized to itsun-ionized form. As a result, the dose of hypnotic agent is rapidly andefficiently absorbed by the oral mucosa with surprisingly lowinter-subject variability in terms of maximum plasma concentration(C_(max)) and the time to reach the maximum plasma concentration(T_(max)). Furthermore, delivery of the hypnotic agent across the oralmucosa advantageously bypasses hepatic first pass metabolism of the drugand avoids enzymatic degradation of the drug within the gastrointestinaltract, resulting in increased bioavailability of the hypnotic agent andreduced time to onset of therapeutic activity as compared to traditionaldosage forms for oral (e.g., tablet) administration. Methods for usingthe compositions of the present invention for treating sleep disorderssuch as various types of insomnia are also provided.

The present invention is based upon the surprising discovery thatsublingual delivery of zolpidem compositions containing the buffersystems described herein provides both increased bioavailability of thetherapeutic agent and reduced time to onset of therapeutic activity thatfar surpass those observed for commercial oral tablets such as Ambien®tablets and buccal tablets such as zolpidem FlashDose® tablets (BiovailTechnologies Ltd.; Chantilly, VA). In fact, it was counterintuitive toexpect that the rapidly disintegrating zolpidem solid dosage formsdescribed herein would provide the rapid absorption and marked increasein bioavailability of zolpidem that was observed. As a result, thezolpidem in the compositions of the present invention reaches thesystemic circulation in a substantially shorter period of time and at asubstantially higher concentration than the zolpidem in either of thecommercial tablet compositions. Thus, the zolpidem compositions of thepresent invention are superior to the commercial tablet compositions inreducing the time to onset of therapeutic activity, maintaining sleep(e.g., total sleep time, number of awakenings), enhancing sleep quality,eliminating the effect of food, and reducing any morning-after residualeffects.

III. Description of the Embodiments

In one aspect, the present invention provides a solid composition fordelivery of a hypnotic agent across the oral mucosa, the compositioncomprising:

-   -   (a) a hypnotic agent selected from the group consisting of an        imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine,        and a pharmaceutically acceptable salt thereof;    -   (b) a carrier that provides complete buccal or sublingual        disintegration in about 5 minutes or less following        administration to the mouth; and    -   (c) a binary buffer system comprising a carbonate salt and a        bicarbonate salt,        wherein the binary buffer system raises the pH of saliva to a pH        greater than about 7.8, irrespective of the starting pH of        saliva.

In certain instances, the binary buffer system raises the pH of salivato a pH greater than about 8.5, irrespective of the starting pH ofsaliva. In certain other instances, the binary buffer system raises thepH of saliva to a pH greater than about 9 (e.g., about 9-11),irrespective of the starting pH of saliva. In one embodiment, theimidazopyridine hypnotic agent is selected from the group consisting ofzolpidem and alpidem. Preferably, the imidazopyridine hypnotic agent iszolpidem. Any form of zolpidem is suitable for use in the compositionsdescribed herein. e.g., a salt form of zolpidem (e.g., zolpidemtartrate), a free base form of zolpidem, or a mixture thereof. Inanother embodiment, the dihydropyrrolopyrazine hypnotic agent iszopeclon. In yet another embodiment, the pyrazolopyrimidine hypnoticagent is selected from the group consisting of zaleplon and indiplon.

In certain instances, the carrier provides complete buccal or sublingualdisintegration in about 2 minutes or less following administration. Incertain other instances, the carrier comprises at least one binder andat least one disintegrating agent in such relative proportion to providea buccal or sublingual disintegration time of about 5 minutes or less,preferably about 2 minutes or less, following administration.Preferably, the ratio of the binder to the disintegrating agent is fromabout 0.1 to about 10.0, more preferably from about 0.1 to about 1.0,and most preferably from about 0.26 to about 0.79. However, one skilledin the art will appreciate that the compositions of the presentinvention can be made without any binders, e.g., to produce a highlyfriable dosage form.

In another embodiment, the carbonate salt is selected from the groupconsisting of sodium carbonate, potassium carbonate, calcium carbonate,ammonium carbonate, and magnesium carbonate. In yet another embodiment,the bicarbonate salt is selected from the group consisting of sodiumbicarbonate, potassium bicarbonate, calcium bicarbonate, ammoniumbicarbonate, and magnesium bicarbonate. In a preferred embodiment, thebinary buffer system comprises sodium carbonate and sodium bicarbonate.In another preferred embodiment, the sodium bicarbonate isdessicant-coated sodium bicarbonate.

In yet another embodiment, the compositions of the present invention arein a dosage form selected from the group consisting of a lozenge, achewing gum, a chewable tablet, and a dissolving tablet such as aslow-dissolving tablet or a quick-dissolving tablet. Preferably, thecomposition is a lozenge or a dissolving tablet. A description oflozenge, chewing gum, chewable tablet, slow-dissolving tablet, andquick-dissolving tablet compositions containing a hypnotic agent isprovided in the Examples below.

In a preferred embodiment, the hypnotic agent is delivered across anoral mucosa selected from the group consisting of the sublingual mucosa,the buccal mucosa, and a combination thereof. In a particularlypreferred embodiment, the composition is administered sublingually sothat the hypnotic agent is delivered across the sublingual mucosa.

In another embodiment, the carrier is selected from the group consistingof a binder, a gum base, and combinations thereof. Suitable binders foruse in the compositions of the present invention include, withoutlimitation, sugar alcohols such as mannitol, sorbitol, and xylitol;sugars such as lactose, dextrose, sucrose, glucose, and powdered sugar;natural gums such as acacia gum, xanthan gum, guar gum, tara gum,mesquite gum, fenugreek gum, locust bean gum, ghatti gum, and tragacanthgum; other substances such as inositol, molasses, maltodextrin, starch,cellulose, microcrystalline cellulose, polyvinylpyrrolidone, alginate,extract of Irish moss, panwar gum, mucilage of isapol husks, Veegum®,larch arabogalactan, gelatin, methylcellulose, ethylcellulose,carboxymethylcellulose, hydroxypropylmethylcellulose, polyacrylic acid(e.g., Carbopol), calcium silicate, calcium phosphate, dicalciumphosphate, calcium sulfate, kaolin, sodium chloride, polyethyleneglycol; and combinations thereof. Suitable gum bases for use in thecompositions of the present invention include, for example, materialsselected from among the many water-insoluble and saliva-insoluble gumbase materials known in the art. In certain instances, the gum basecomprises at least one hydrophobic polymer and at least one hydrophilicpolymer. Non-limiting examples of suitable hydrophobic and hydrophilicpolymers for gum bases include both natural and synthetic polymers suchas elastomers, rubbers, and combinations thereof. Examples of suitablenatural polymers include, without limitation, substances of plant originsuch as chicle, jelutong, gutta percha, crown gum, and combinationsthereof. Examples of suitable synthetic polymers include elastomers suchas butadiene-styrene copolymers, isobutylene and isoprene copolymers(e.g., “butyl rubber”), polyethylene, polyisobutylene, polyvinylester(e.g., polyvinyl acetate and polyvinyl acetate phthalate), andcombinations thereof. In other instances, the gum base comprises amixture of butyl rubber (i.e., isobutylene and isoprene copolymer),polyisobutylene, and optionally, polyvinylacetate (e.g., having amolecular weight of approximately 12,000).

In yet another embodiment, the compositions of the present invention canfurther comprise a sweetening agent, a flavoring agent, a protectingagent, a plasticizer, a wax, an elastomeric solvent, a filler material,a preservative, or combinations thereof. In still yet anotherembodiment, the compositions of the present invention can furthercomprise a lubricating agent, a wetting agent, an emulsifying agent, asolubilizing agent, a suspending agent, a coloring agent, adisintegrating agent, or combinations thereof. In a preferredembodiment, the average particle size of the drug in the compositionsdescribed herein is about 20 microns, as compared to a typical averagedrug particle size of from about 75 to about 100 microns. In anotherpreferred embodiment, the average particle size of the drug in thecompositions described herein is less than or equal to the averageparticle size of the carrier ingredients (e.g., gum base, binders,etc.).

In preferred embodiments of the present invention, the hypnotic agent iszolpidem and the binary buffer system comprises sodium carbonate andsodium bicarbonate. Such compositions are preferably formulated in theform of a lozenge, candy, or dissolving tablet (e.g., slow-dissolvingtablet or quick-dissolving tablet) for sublingual administration. As aresult, upon sublingual administration, zolpidem is delivered across thesublingual mucosa. In other preferred embodiments, the sodiumbicarbonate is dessicant-coated sodium bicarbonate. A combined weightpercent of sodium carbonate and sodium bicarbonate that is greater thanor equal to the weight percent of zolpidem is also preferred.

In certain instances, the composition comprises from about 1.0 to about5.5 weight percent zolpidem; from about 6.0 to about 10.0 weight percentsodium carbonate; and from about 9.0 to about 13.0 weight percentdessicant-coated sodium bicarbonate. In a preferred embodiment, thecomposition comprises about 4.5 weight percent zolpidem; about 8.0weight percent sodium carbonate; and about 11.0 weight percentdessicant-coated sodium bicarbonate. Such compositions are preferably inthe form of a lozenge or candy with a mass of from about 100 to about300 mg, e.g., about 100, 110, 120, 130, 140, 150, 160, 170, 180, 190,200, 210, 220, 230, 240, 250, 260, 270, 280, 290, and 300 mg. Thelozenges or candies dissolve in a subject's month at a very rapid rate,e.g., within about 2-3 minutes following administration.

In certain other instances, the composition comprises from about 1.0 toabout 5.0 weight percent zolpidem; from about 5.0 to about 9.0 weightpercent sodium carbonate; and from about 7.0 to about 11.0 weightpercent sodium bicarbonate. In a preferred embodiment, the compositioncomprises about 4.0 weight percent zolpidem; about 7.0 weight percentsodium carbonate; and about 9.0 weight percent sodium bicarbonate. Suchcompositions are preferably in the form of a dissolving tablet such as aslow-dissolving tablet or a quick-dissolving tablet of from about 100 toabout 300 mg, e.g., about 100, 110, 120, 130, 140, 150, 160, 170, 180,190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, and 300 mg. Thequick-dissolving tablets dissolve in a subject's mouth at a rapid rate,e.g., within about 5 minutes following administration, and theslow-dissolving tablets dissolve in a subject's mouth at a slower rate,e.g., within about 10 minutes following administration.

In another aspect, the present invention provides a composition fordelivery of a hypnotic agent across the oral mucosa, the compositioncomprising:

-   -   (a) a hypnotic agent selected from the group consisting of an        imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine,        and a pharmaceutically acceptable salt thereof;    -   (b) a carrier; and    -   (c) a binary buffer system comprising a carbonate salt and a        bicarbonate salt,        wherein the binary buffer system raises the pH of saliva to a pH        greater than about 7.8, irrespective of the starting pH of        saliva.

In certain instances, the binary buffer system raises the pH of salivato a pH greater than about 8.5, irrespective of the starting pH ofsaliva. In certain other instances, the binary buffer system raises thepH of saliva to a pH greater than about 9 (e.g., about 9-11),irrespective of the starting pH of saliva. Suitable imidazopyridine,dihydropyrrolopyrazine, and pyrazolopyrimidine hypnotic agents for usein the present invention are described above. Suitable carbonate saltsand bicarbonate salts for use in the binary buffer systems of thepresent invention are also described above.

In another embodiment, the compositions of the present invention are inany of the dosage forms described above. Preferably, the hypnotic agentis delivered across an oral mucosa as described above. In yet anotherembodiment, the carrier is selected from the group consisting of abinder, a gum base, and combinations thereof. Suitable binders and gumbases for use in the compositions of the present invention are describedabove. In certain instances, the carrier provides a buccal or sublingualdisintegration time of about 10 minutes or less, preferably about 5minutes or less, and more preferably about 2 minutes or less, followingadministration. In certain other instances, the carrier comprises atleast one binder and at least one disintegrating agent in such relativeproportion to provide a buccal or sublingual disintegration time ofabout 10 minutes or less, preferably about 5 minutes or less, and morepreferably about 2 minutes or less, following administration.

In yet another embodiment, the compositions of the present invention canfurther comprise one or more of the additional agents described above.In preferred embodiments, the average particle size of the drug in thecompositions described herein is about 20 microns and/or is less than orequal to the average particle size of the carrier ingredients (e.g., gumbase, binders, etc.).

In other preferred embodiments of the present invention, the hypnoticagent is zolpidem and the binary buffer system comprises sodiumcarbonate and sodium bicarbonate. Preferred amounts of each of thesecomponents are described above, along with preferred dosage forms andtheir preferred weight.

In yet another aspect, the present invention provides a composition fordelivery of a hypnotic agent across the oral mucosa, the compositioncomprising:

-   -   (a) a hypnotic agent selected from the group consisting of an        imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine,        and a pharmaceutically acceptable salt thereof;    -   (b) a carrier; and    -   (c) a binary buffer system comprising a carbonate salt or a        bicarbonate salt and a second buffering agent,        wherein the binary buffer system raises the pH of saliva to a pH        greater than about 7.8, irrespective of the starting pH of        saliva.

In certain instances, the binary buffer system raises the pH of salivato a pH greater than about 8.5, irrespective of the starting pH ofsaliva. In certain other instances, the binary buffer system raises thepH of saliva to a pH greater than about 9 (e.g., about 9-11),irrespective of the starting pH of saliva. Suitable imidazopyridine,dihydropyrrolopyrazine, and pyrazolopyrimidine hypnotic agents for usein the present invention are described above. Suitable carbonate saltsand bicarbonate salts for use in the binary buffer systems of thepresent invention are also described above.

In one embodiment, the second buffering agent is selected from the groupconsisting of a metal oxide, a citrate salt, a phosphate salt, a boratesalt, an ascorbate salt, an acetate salt, and alkaline starch. Suitablemetal oxides include, without limitation, magnesium oxide and aluminumoxide. Preferably, the magnesium oxide is amorphous magnesium oxide.Suitable citrate, phosphate, and borate salts include, withoutlimitation, any salt of citric acid, phosphoric acid, or boric acidknown in the art. For example, in some embodiments, the citrate salt isselected from the group consisting of sodium citrate, potassium citrate,calcium citrate, magnesium citrate, and ammonium citrate. In otherembodiments, the phosphate salt is selected from the group consisting ofmonobasic sodium phosphate, dibasic sodium phosphate, monobasicpotassium phosphate, dibasic potassium phosphate, monobasic calciumphosphate, dibasic calcium phosphate, monobasic magnesium phosphate,dibasic magnesium phosphate, monobasic ammonium phosphate, and dibasicammonium phosphate. In yet other embodiments, the borate salt isselected from the group consisting of sodium borate, potassium borate,calcium borate, magnesium borate, and ammonium borate. In certaininstances, the binary buffer system comprises a carbonate salt and ametal oxide, a citrate salt, a phosphate salt, or a borate salt. Incertain other instances, the binary buffer system comprises abicarbonate salt and a metal oxide, a citrate salt, a phosphate salt, ora borate salt.

In another embodiment, the compositions of the present invention are inany of the dosage forms described above. Preferably, the hypnotic agentis delivered across an oral mucosa, as described above. In yet anotherembodiment, the carrier is selected from the group consisting of abinder, a gum base, and combinations thereof. Suitable binders and gumbases for use in the compositions of the present invention are describedabove. In certain instances, the carrier provides a buccal or sublingualdisintegration time as described above. In certain other instances, thecarrier comprises at least one binder and at least one disintegratingagent as described above.

In yet another embodiment, the compositions of the present invention canfurther comprise one or more of the additional agents described above.In preferred embodiments, the average particle size of the drug in thecompositions described herein is about 20 microns and/or is less than orequal to the average particle size of the carrier ingredients (e.g., gumbase, binders, etc.).

In preferred embodiments of the present invention, the hypnotic agent iszolpidem and the binary buffer system comprises sodium carbonate orsodium bicarbonate and a second buffering agent. Such compositions arepreferably formulated in the form of a lozenge, candy, or dissolvingtablet for sublingual administration.

In still yet another aspect, the present invention provides acomposition for delivery of a hypnotic agent across the oral mucosa, thecomposition comprising:

-   -   (a) a hypnotic agent selected from the group consisting of an        imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine,        and a pharmaceutically acceptable salt thereof;    -   (b) a carrier; and    -   (c) a binary buffer system comprising a metal oxide and a        citrate, phosphate, or borate salt,        wherein the binary buffer system raises the pH of saliva to a pH        greater than about 7.8, irrespective of the starting pH of        saliva.

In certain instances, the binary buffer system raises the pH of salivato a pH greater than about 8.5, irrespective of the starting pH ofsaliva. In certain other instances, the binary buffer system raises thepH of saliva to a pH greater than about 9 (e.g., about 9-11),irrespective of the starting pH of saliva. Suitable imidazopyridine,dihydropyrrolopyrazine, and pyrazolopyrimidine hypnotic agents for usein the present invention are described above.

Suitable metal oxides include, without limitation, magnesium oxide andaluminum oxide. Suitable citrate, phosphate, and borate salts include,without limitation, any salt of citric acid, phosphoric acid, or boricacid known in the art such as those described above. In certaininstances, the binary buffer system comprises a metal oxide and acitrate salt. In certain other instances, the binary buffer systemcomprises a metal oxide and a phosphate salt. In further instances, thebinary buffer system comprises a metal oxide and a borate salt.

In one embodiment, the compositions of the present invention are in anyof the dosage forms described above. Preferably, the hypnotic agent isdelivered across an oral mucosa as described above. In yet anotherembodiment, the carrier is selected from the group consisting of abinder, a gum base, and combinations thereof. Suitable binders and gumbases for use in the compositions of the present invention are describedabove. In certain instances, the carrier provides a buccal or sublingualdisintegration time as described above. In certain other instances, thecarrier comprises at least one binder and at least one disintegratingagent as described above.

In another embodiment, the compositions of the present invention canfurther comprise one or more of the additional agents described above.In preferred embodiments, the average particle size of the drug in thecompositions described herein is about 20 microns and/or is less than orequal to the average particle size of the carrier ingredients (e.g., gumbase, binders, etc.).

In preferred embodiments of the present invention, the hypnotic agent iszolpidem and the binary buffer system comprises amorphous magnesiumoxide and a citrate, phosphate, or borate salt. Salt composition arepreferably formulated in the form of a lozenge, candy, or dissolvingtablet for sublingual administration.

In a further aspect, the present invention provides a composition fordelivery of a hypnotic agent across the oral mucosa, the compositioncomprising:

-   -   (a) a hypnotic agent selected from the group consisting of an        imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine,        and a pharmaceutically acceptable salt thereof;    -   (b) a carrier; and    -   (c) a ternary buffer system comprising a carbonate salt, a        bicarbonate salt, and a third buffering agent,        wherein the ternary buffer system raises the pH of saliva to a        pH greater than about 7.8, irrespective of the starting pH of        saliva.

In certain instances, the binary buffer system raises the pH of salivato a pH greater than about 8.5, irrespective of the starting pH ofsaliva. In certain other instances, the binary buffer system raises thepH of saliva to a pH greater than about 9 (e.g., about 9-11),irrespective of the starting pH of saliva. Suitable imidazopyridine,dihydropyrrolopyrazine, and pyrazolopyrimidine hypnotic agents for usein the present invention are described above. Suitable carbonate saltsand bicarbonate salts for use in the ternary buffer systems of thepresent invention are also described above.

In one embodiment, the third buffering agent is selected from the groupconsisting of a metal oxide, a citrate salt, a phosphate salt, a boratesalt, an ascorbate salt, an acetate salt, and alkaline starch. Suitablemetal oxides include, without limitation, magnesium oxide and aluminumoxide. Suitable citrate, phosphate, and borate salts include, withoutlimitation, any salt of citric acid, phosphoric acid, or boric acidknown in the art such as those described above. In certain instances,the ternary buffer system comprises a carbonate salt, a bicarbonatesalt, and a metal oxide. In certain other instances, the ternary buffersystem comprises a carbonate salt, a bicarbonate salt, and a citrate,phosphate, or borate salt.

In another embodiment, the compositions of the present invention are inany of the dosage forms described above. Preferably, the hypnotic agentis delivered across an oral mucosa as described above. In yet anotherembodiment, the carrier is selected from the group consisting of abinder, a gum base, and combinations thereof. Suitable binders and gumbases for use in the compositions of the present invention are describedabove. In certain instances, the carrier provides a buccal or sublingualdisintegration time as described above. In certain other instances, thecarrier comprises at least one binder and at least one disintegratingagent as described above.

In yet another embodiment, the compositions of the present invention canfurther comprise one or more of the additional agents described above.In preferred embodiments, the average particle size of the drug in thecompositions described herein is about 20 microns and/or is less than orequal to the average particle size of the carrier ingredients (e.g., gumbase, binders, etc.).

In preferred embodiments of the present invention, the hypnotic agent iszolpidem and the ternary buffer system comprises sodium carbonate,sodium bicarbonate, and a third buffering agent. Such compositions arepreferably formulated in the form of a lozenge, candy, or dissolvingtablet for sublingual administration. In instances where the thirdbuffering agent is a metal oxide, a weight percent of the metal oxidethat is greater than the combined weight percent of sodium carbonate andsodium bicarbonate is preferred.

In another aspect, the present invention provides a composition fordelivery of a hypnotic agent across the oral mucosa, the compositioncomprising:

-   -   (a) a hypnotic agent selected from the group consisting of an        imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine,        and a pharmaceutically acceptable salt thereof;    -   (b) a carrier; and    -   (c) a buffer system comprising a carbonate salt or a bicarbonate        salt and two or more buffering agents selected from the group        consisting of a metal oxide, a citrate salt, a phosphate salt,        and a borate salt,        wherein the buffer system raises the pH of saliva to a pH        greater than about 7.8, irrespective of the starting pH of        saliva.

In certain instances, the binary buffer system raises the pH of salivato a pH greater than about 8.5, irrespective of the starting pH ofsaliva. In certain other instances, the binary buffer system raises thepH of saliva to a pH greater than about 9 (e.g., about 9-11),irrespective of the starting pH of saliva. Suitable imidazopyridine,dihydropyrrolopyrazine, and pyraxolopyrimidine hypnotic agents for usein the present invention are described above. Suitable carbonate saltsand bicarbonate salts for use in the buffer systems of the presentinvention are also described above.

Suitable metal oxides include, without limitation, magnesium oxide andaluminum oxide. Suitable citrate, phosphate, and borate salts include,without limitation, any salt of citric acid, phosphoric acid, or boricacid known in the art such as those described above. In certaininstances, the buffer system comprises a carbonate salt or a bicarbonatesalt, a metal oxide, and a citrate, phosphate, or borate salt. Incertain other instances, the buffer system comprises a carbonate salt ora bicarbonate salt, a citrate salt, and a phosphate salt. In certaininstances, the buffer system comprises a carbonate salt or a bicarbonatesalt, a citrate salt, and a borate salt. In certain other instances, thebuffer system comprises a carbonate salt or a bicarbonate salt, aphosphate salt, and a borate salt.

In one embodiment, the compositions of the present invention are in anyof the dosage forms described above. Preferably, the hypnotic agent isdelivered across an oral mucosa as described above. In yet anotherembodiment, the carrier is selected from the group consisting of abinder, a gum base, and combinations thereof. Suitable binders and gambases for use in the compositions of the present invention are describedabove. In certain instances, the carrier provides a buccal or sublingualdisintegration time as described above. In certain other instances, thecarrier comprises at least one binder and at least one disintegratingagent as described above.

In another embodiment, the compositions of the present invention canfurther comprise one or more of the additional agents described above.In preferred embodiments, the average particle size of the drug in thecompositions described herein is about 20 microns and/or is less than orequal to the average particle size of the carrier ingredients (e.g., gumbase, binders, etc.).

In preferred embodiments of the present invention, the hypnotic agent iszolpidem and the buffer system comprises sodium carbonate or sodiumbicarbonate and two or more buffering agents selected from the groupconsisting of a metal oxide, a citrate salt, a phosphate salt, and aborate salt. Such compositions are preferably formulated in the form ofa lozenge, candy, or dissolving tablet for sublingual administration.

In yet another aspect, the present invention provides a method fortreating a sleep disorder in a subject in need thereof, the methodcomprising:

administering to the subject a composition comprising a therapeuticallyeffective amount of a hypnotic agent selected from the group consistingof an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine,and a pharmaceutically acceptable salt thereof; a carrier; and a binarybuffer system comprising a carbonate salt and a bicarbonate salt,wherein the binary buffer system raises the pH of saliva to a pH greaterthan about 7.8, irrespective of the starting pH of saliva.

In a preferred embodiment, the composition delivers the hypnotic agentacross the oral mucosa such as, for example, the sublingual mucosa, thebuccal mucosa, or a combination thereof. In a particularly preferredembodiment, the composition is administered sublingually so that thehypnotic agent is delivered across the sublingual mucosa. Suitable sleepdisorders that can be treated with the compositions of the presentinvention include, without limitation, insomnia such as transientinsomnia, short-term insomnia, and chronic insomnia.

In certain instances, the binary buffer system raises the pH of salivato a pH greater than about 8.5, irrespective of the starting pH ofsaliva. In certain other instances, the binary buffer system raises thepH of saliva to a pH greater than about 9 (e.g., about 9-11),irrespective of the starting pH of saliva. Suitable imidazopyridine,dihydropyrrolopyrazine, and pyrazolopyrimidine hypnotic agents for usein the present invention are described above. Suitable carbonate saltsand bicarbonate salts for use in the binary buffer systems of thepresent invention are also described above.

In addition to a binary buffer system comprising a carbonate salt and abicarbonate salt, other buffer systems are suitable for use in thecompositions of the present invention. For example, in an alternativeembodiment, the binary buffer system comprises a carbonate salt or abicarbonate salt and a second buffering agent such as a metal oxide, acitrate salt, a phosphate salt, a borate salt, an ascorbate salt, anacetate salt, and alkaline starch. In another alternative embodiment,the binary buffer system comprises a metal oxide and a citrate,phosphate, or borate salt. In yet another alternative embodiment, thebuffer system is a ternary buffer system comprising a carbonate salt, abicarbonate salt, and a third buffering agent such as a metal oxide, acitrate salt, a phosphate salt, a borate salt, an ascorbate salt, anacetate salt, and alkaline starch. In still yet another alternativeembodiment, the buffer system comprises a carbonate salt or abicarbonate salt and two or more buffering agents selected from thegroup consisting of a metal oxide, a citrate salt, a phosphate salt, anda borate salt.

In one embodiment, the compositions of the present invention are in anyof the dosage forms described above. Preferably, the hypnotic agent isdelivered across an oral mucosa as described above. In yet anotherembodiment, the carrier is selected from the group consisting of abinder, a gum base, and combinations thereof. Suitable binders and gumbases for use in the compositions of the present invention are describedabove. In certain instances, the carrier provides a buccal or sublingualdisintegration time as described above. In certain other instances, thecarrier comprises at least one binder and at least one disintegratingagent as described above.

In another embodiment, the compositions of the present invention canfurther comprise one or more of the additional agents described above.In preferred embodiments, the average particle size of the drug in thecompositions described herein is about 20 microns and/or is less than orequal to the average particle size of the carrier ingredients (e.g., gumbase, binders, etc.).

In preferred embodiments, of the present invention, the hypnotic agentis zolpidem and the binary buffer system comprises sodium carbonate andsodium bicarbonate. Preferred amounts of each of these components aredescribed above, along with preferred dosage forms and their preferredweight.

A. Hypnotic Agents

The hypnotic agents of the present invention are preferably selectedfrom an imidazopyridine compound such as zolpidem or alpidem; adihydropyrrolopyrazine compound such as zopeclon; a pyrazolopyrimidinecompound such as zaleplon or indiplon; pharmaceutically acceptable saltsthereof; and combinations thereof. More preferably, the hypnotic agentis zolpidem, in all suitable forms.

In general, the hypnotic agents of the present invention are basiccompounds having an ionized form and an un-ionized form. In certaininstances, the hypnotic agent is initially present at least partly in anionized form. In certain other instances, the hypnotic agent isinitially present in an un-ionized form. As described in more detailbelow, the buffer system of the compositions described herein helps toconvert substantially all of the hypnotic agent from its ionized form toits un-ionized form. Alternatively, the buffer system helps ensure thatthe hypnotic agent, initially in an un-ionized form, remains in anun-ionized form.

As used herein, the term “hypnotic agent” includes all pharmaceuticallyacceptable forms of the hypnotic agent being described. For example, thehypnotic agent can be in a racemic or isomeric mixture, a solid complexbound to an ion exchange resin, or the like. In addition, the hypnoticagent can be in a solvated form. The term “hypnotic agent” is alsointended to include all pharmaceutically acceptable salts, derivatives,and analogs of the hypnotic agent being described, as well ascombinations thereof. For example, the pharmaceutically acceptable saltsof the hypnotic agent include, without limitation, the tartrate,succinate, tartarate, bitartarate, dihydrochloride, salicylate,hemisuccinate, citrate, maleate, hydrochloride, carbamate, sulfate,nitrate, and benzoate salt forms thereof, as well as combinationsthereof and the like. Any form of the hypnotic agent is suitable for usein the compositions of the present invention, e.g., a pharmaceuticallyacceptable salt of the hypnotic agent (e.g., zolpidem tartrate), a freebase of the hypnotic agent or a mixture thereof.

Conversion of the ionized form to the un-ionized form for the hypnoticagent is related to pH according to the formula: pH=pKa+Log₁₀(un-ionized concentration/ionized concentration). When the pH is thesame as the pKa, equimolar concentrations of the un-ionized form andionized form exist. For basic compounds such as the hypnotic agentsdescribed herein, when the pH is one unit higher than the pKa, the ratioof the un-ionized form to the ionized form is 91:9. Similarly, when thepH is two units higher than the pKa, the ratio of un-ionized form to theionized form is 100:1. As noted above, the un-ionized form is lipophilicand, therefore, more capable of passing through mucous membranes such asthe oral mucosa than the ionized form. which is lipophobic in nature.Accordingly, increasing the pH of the saliva favors conversion of theionized form into the un-ionized form for basic compounds such as thehypnotic agents described herein, and the final pH can be determined bymaking use of the above formula.

The hypnotic agents of the present invention are selected from the classof compounds in the imidazopyridine, dihydropyrrolopyrazine, orpyraxolopyrimidine family and are useful in the treatment of conditionssuch as sleep disorders. Illustrative examples of suitableimidazopyridine compounds for use in the present invention are zolpidem,alpidem, pharmaceutically acceptable salts thereof, analogs thereof, andderivatives thereof. These imidazopyridine compounds each have animidazopyridine group, as shown below:

For the imidazopyridine compounds, the nitrogen in the imidazole portionof the bicyclic ring of the structure controls the extent of ionizationand the degree of lipophilicity in any given medium. Typically thenitrogen in the imidazole portion imparts a pKa of from about 6.8 toabout 7.5 to the molecule. Therefore, using the above formula, it can bedemonstrated that about 90% conversion to an un-ionized form can beachieved for these compounds at a pH of from about 7.8 to about 8.5.

Illustrative examples of suitable dihydropyrrolopyrazine compounds foruse in the present invention are zopeclon, pharmaceutically acceptablesalts thereof, analogs thereof, and derivatives thereof. Thesedihydropyrrolopyrrolopyrazines each have a dihydropyrrolopyrazine group,as shown below:

Illustrative examples of suitable pyrazolopyrimidine compounds for usein the present invention are zaleplon, indiplon, pharmaceuticallyacceptable salts thereof, analogs thereof, and derivatives thereof.These pyrazolopyrimidines each have a pyrazolopyrimidine group, as shownbelow;

For the pyrazolopyrimidine compounds, the nitrogen in the pyrimidinegroup controls the extent of ionization and the degree of lipophilicityin any given medium. Typically, the nitrogen in the pyrimidine groupimparts a pKa of from about 8 to about 9 to the molecule. Therefore,using the above formula, it can be demonstrated that about 90%conversion to an un-ionized form can be achieved for these compounds ata pH of from about 9 to about 10.

In general, the hypnotic agents of the present invention act asbenzodiazepine receptor agonists. Preferably, the hypnotic agentsselectively bind to the benzodiazepine₁ receptor. Without being bound toany particular theory, the therapeutic activity of the hypnotic agentsof the present invention in treating sleep disorders is attributed to anenhancement of the inhibitory action of gamma-aminobutyric acid (GABA)in the central nervous system.

B. Buffer Systems

The buffer systems of the compositions described herein are capable ofraising the pH of saliva to a pH greater than about 7.8, irrespective ofthe starting pH of saliva. In this way, the buffer system helps convertsubstantially all of the hypnotic agent from its ionized form to itsun-ionized form. Alternatively, the buffer system helps ensure that thehypnotic agent, initially in an un-ionized form, remains in anun-ionized form. Although basic buffering agents are typically used inthe buffer systems of the present invention, one skilled in the art willappreciate that acidic agents can also be used to adjust the pH of thebuffer system as long as the buffer system as a whole raises the pH ofsaliva to a pH greater than about 7.8.

In one embodiment, the present invention provides binary buffer systemscomprising a carbonate salt and a bicarbonate salt. The concentration ofeach buffer system component is tailored such that the final salivary pHis achieved and sustained for a period of time, e.g., for at least about2 minutes, at least about 5 minutes, at least about 10 minutes, at leastabout 20 minutes, or at least about 60 minutes. This typically involvesa sensory and safety trial and error type of procedure of adding variousamounts of each buffer system component and then measuring the final pHover time. In this way, selection of an appropriate weight ratio foreach buffer system component can be easily determined in just a fewtrials. For example, the weight ratio of carbonate salt to bicarbonatesalt can be from about 1:10 to about 10:1, preferably from about 1:5 toabout 5:1, more preferably from about 1:3 to about 3:1, and still morepreferably from about 1:2 to about 2:1.

The carbonate salt is generally selected from sodium carbonate,potassium carbonate, calcium carbonate, ammonium carbonate, andmagnesium carbonate. Preferably, the carbonate salt is sodium carbonateor potassium carbonate. Most preferably, the carbonate salt is sodiumcarbonate. Similarly, the bicarbonate salt is generally selected fromsodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammoniumbicarbonate, and magnesium bicarbonate. Preferably, the bicarbonate saltis sodium bicarbonate or potassium bicarbonate, Most preferably, thebicarbonate salt is sodium bicarbonate. In some embodiments, adessicant-coated sodium bicarbonate is preferred. The amount ofcarbonate salt and bicarbonate salt used in the binary buffer system isan amount that is sufficient to raise salivary pH to a pH of about 7.8or more, preferably about 8.5 or more, and more preferably about 9 ormore (e.g., about 9-11), irrespective of the starting pH.

In certain instances, the amount of bicarbonate salt is greater than orequal to the amount of carbonate salt, and the weight ratio of carbonatesalt to bicarbonate salt is from about 1:1 to about 1:10, preferablyfrom about 1:1 to about 1:5, and more preferably from about 1:1 to about1:2, e.g., 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8,1:1.9, or 1:2. Alternatively, the amount of bicarbonate salt is lessthan or equal to the amount of carbonate salt, and the weight ratio ofcarbonate salt to bicarbonate salt is from about 1:1 to about 10:1,preferably from about 1:1 to about 5:1, and more preferably from about1:1 to about 2:1, e.g., 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1,1.7:1, 1.8:1, 1.9:1, or 2:1. In certain other instances, the combinedamount of carbonate salt and bicarbonate salt is greater than or equalto the amount of the hypnotic agent, and the weight ratio of carbonatesalt and bicarbonate salt to hypnotic agent is preferably from about 1:1to about 10:1, e.g., 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or10:1. Alternatively, the combined amount of carbonate salt andbicarbonate salt is less than or equal to the amount of the hypnoticagent, and the weight ratio of carbonate salt and bicarbonate salt tohypnotic agent is preferably from about 1:1 to about 1:10, e.g., 1:1,1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

In view of the above, the buffer systems of the present invention, insome of the most preferred embodiments, are binary buffer systemscontaining sodium carbonate and sodium bicarbonate.

Alternatively, in another embodiment, the buffer systems of the presentinvention are binary buffer systems comprising a carbonate salt or abicarbonate salt and a second buffering agent. The concentration of eachbuffer system component is tailored such that the final salivary pH isachieved and sustained for a period of time, e.g., for at least about 2minutes, at least about 5 minutes, at least about 10 minutes, at leastabout 20 minutes, or at least about 60 minutes.

Suitable carbonate salts and bicarbonate salts are described above. Theamount of carbonate salt or bicarbonate salt used in the binary buffersystem is an amount that is sufficient, when used with the secondbuffering agent, to raise salivary pH to a pH of about 7.8 or more,preferably about 8.5 or more, and more preferably about 9 or more (e.g.,about 9-11), irrespective of the starting pH. In certain instances, theamount of the second buffering agent in the binary buffer system isgreater than or equal to the amount of the carbonate salt or bicarbonatesalt. For example, the weight ratio of the second buffering agent to thecarbonate salt or bicarbonate salt can be from about 1:1 to about 10:1,preferably from about 1:1 to about 5:1, and more preferably from about1:1 to about 3:1. In certain other instances, the amount of the secondbuffering agent in the binary buffer system is less than or equal to theamount of the carbonate salt or bicarbonate salt. For example, theweight ratio of the second buffering agent to the carbonate salt orbicarbonate salt can be from about 1:1 to about 1:10, preferably fromabout 1:1 to about 1:5, and more preferably from about 1:1 to about 1:3.

The second buffering agent is generally selected from a metal oxide suchas magnesium oxide or aluminum oxide; a citrate salt such as sodiumcitrate, potassium citrate, calcium citrate, magnesium citrate, andammonium citrate; a phosphate salt such as monobasic sodium phosphate,dibasic sodium phosphate, monobasic potassium phosphate, dibasicpotassium phosphate, monobasic calcium phosphate, dibasic calciumphosphate, monobasic magnesium phosphate, dibasic magnesium phosphate,monobasic ammonium phosphate, and dibasic ammonium phosphate; a boratesalt such as sodium borate, potassium borate, calcium borate, magnesiumborate, and ammonium borate; an ascorbate salt such as potassiumascorbate or sodium ascorbate; an acetate salt such as potassium acetateor sodium acetate; and alkaline starch. However, one skilled in the artwill appreciate that any metal oxide or salt of citric acid, phosphoricacid, boric acid, ascorbic acid, or acetic acid is suitable for use inthe buffer systems of the present invention. The amount of the secondbuffering agent used in the binary buffer system is an amount that issufficient, when used with the carbonate salt or bicarbonate salt, toraise salivary pH to a pH of about 7.8 or more, preferably about 8.5 ormore, and more preferably about 9 or more (e.g., about 9-11),irrespective of the starting pH. In some embodiments, a metal oxide suchas magnesium oxide or aluminum oxide is the preferred second bufferingagent. In a particularly preferred embodiment, the metal oxide isamorphous magnesium oxide.

Alternatively, in yet another embodiment, the buffer systems of thepresent invention are binary buffer systems comprising a metal oxide anda citrate, phosphate, or borate salt. The concentration of each buffersystem component is tailored such that the final salivary pH is achievedand sustained for a period of time, e.g., for at least about 2 minutes,at least 5 about minutes, at least about 10 minutes, at least about 20minutes, or at least about 60 minutes.

Suitable metal oxides include, without limitation, magnesium oxide andaluminum oxide. Suitable citrate, phosphate, and borate salts include,without limitation, essentially any salt of citric acid, phosphoricacid, or boric acid known in the art such as those described above. Incertain instances, the binary buffer system comprises a metal oxide anda citrate salt. In certain other instances, the binary buffer systemcomprises a metal oxide and a phosphate salt. In further instances, thebinary buffer system comprises a metal oxide and a borate salt. Theamount of the metal oxide used in the binary buffer system in an amountthat is sufficient, when used with the citrate, phosphate, or boratesalt, to raise salivary pH to a pH of about 7.8 or more, preferablyabout 8.5 or more, and more preferably about 9 or more (e.g., about9-11), irrespective of the starting pH. Similarly, the amount of thecitrate, phosphate, or borate salt used in the binary buffer system isan amount that is sufficient, when used with the metal oxide, to raisesalivary pH to a pH of about 7.8 or more, preferably about 8.5 or more,and more preferably about 9 or more (e.g., about 9-11), irrespective ofthe starting pH.

In certain instances, the amount of the metal oxide in the binary buffersystem is greater than or equal to the amount of the citrate, phosphate,or borate salt. For example, the weight ratio of the metal oxide to thecitrate, phosphate, or borate salt can be from about 1:1 to about 10:1,preferably from about 1:1 to about 5:1, and more preferably from about1:1 to about 3:1. In certain other instances, the amount of the metaloxide in the binary buffer system is less than or equal to the amount ofthe citrate, phosphate, or borate salt. For example, the weight ratio ofthe metal oxide to the citrate, phosphate, or borate salt can be fromabout 1:1 to about 1:10, preferably from about 1:1 to about 1:5, andmore preferably from about 1:1 to about 1:3.

Alternatively, in still yet another embodiment, the buffer systems ofthe present invention are ternary buffer systems comprising a carbonatesalt, a bicarbonate salt, and a third buffering agent. The concentrationof each buffer system component is tailored such that the final salivarypH is achieved and sustained for a period of time, e.g., for at leastabout 2 minutes, at least 5 about minutes, at least about 10 minutes, atleast about 20 minutes, or at least about 60 minutes. The proceduredescribed above for determining an appropriate weight ratio for eachbuffer system component can also be applied to ternary buffer systems.

Suitable carbonate salts and bicarbonate salts are described above. Theamount of carbonate salt and bicarbonate salt used in the ternary buffersystem is an amount that is sufficient, when used with the thirdbuffering agent, to raise salivary pH to a pH of about 7.8 or more,preferably about 8.5 or more, and more preferably about 9 or more (e.g.,about 9-11), irrespective of the starting pH.

The third buffering agent is generally selected from a metal oxide, acitrate salt, a phosphate salt, a borate salt, an ascorbate salt such aspotassium ascorbate or sodium ascorbate, an acetate salt such aspotassium acetate or sodium acetate, and alkaline starch. Suitable metaloxides include, without limitation, magnesium oxide and aluminum oxide.Suitable citrate, phosphate, and borate salts include, withoutlimitation, any salt of citric acid, phosphoric acid, or boric acidknown in the art such as those described above. The amount of the thirdbuffering agent used in the ternary buffer system is an amount that issufficient, when used with the remaining components, to raise salivarypH to a pH of about 7.8 or more, preferably about 8.5 or more, and morepreferably about 9 or more (e.g., about 9-11), irrespective of thestarting pH. In some embodiments, a metal oxide such as magnesium oxideor aluminum oxide is the preferred third buffering agent. In aparticularly ppreferred embodiment, the metal oxide is amorphousmagnesium oxide.

In certain instances, the amount of the carbonate salt or bicarbonatesalt in the ternary buffer system is greater than or equal to the amountof the third buffering agent. For example, the weight ratio of thecarbonate salt or bicarbonate salt to the third buffering agent can befrom about 1:1 to about 10:1, preferably from about 1:1 to about 5:1,and more preferably from about 1:1 to about 3:1. In certain otherinstances, the amount of the carbonate salt or bicarbonate salt in theternary buffer system is less than or equal to the amount of the thirdbuffering agent. For example, the weight ratio of the carbonate salt orbicarbonate salt to the third buffering agent can be from about 1:1 toabout 1:10, preferably from about 1:1 to about 1:5, and more preferablyfrom about 1:1 to about 1:3.

The ternary buffer systems of the present invention, in some of the mostpreferred embodiments, contain sodium carbonate, sodium bicarbonate, andamorphous magnesium oxide. In certain instances, the amount of sodiumbicarbonate is greater than or equal to the amount of sodium carbonate.For example, the weight ratio of sodium bicarbonate to sodium carbonatecan be from about 1:1 to about 10:1, preferably from about 1:1 to about5:1, and more preferably from about 1:1 to about 3:1. In certain otherinstances, the amount of amorphous magnesium oxide is greater than orequal to the combined amount of sodium carbonate and sodium bicarbonate.For example, the weight ratio of amorphous magnesium oxide to sodiumcarbonate and sodium bicarbonate can be from about 1:1 to about 10:1,preferably from about 1:1 to about 5:1, and more preferably from about1:1 to about 3:1.

Alternatively, in a further embodiment, the buffer systems of thepresent invention are buffer systems comprising a carbonate salt or abicarbonate salt and two or more buffering agents selected from thegroup consisting of a metal oxide, a citrate salt, a phosphate salt, anda borate salt. The concentration of each buffer system component istailored such that the final salivary pH is achieved and sustained for aperiod of time, e.g., for at least about 2 minutes, at least 5 aboutminutes, at least about 10 minutes, at least about 20 minutes, or atleast about 60 minutes.

Suitable carbonate salts and bicarbonate salts are described above. Theamount of carbonate salt or bicarbonate salt used in the buffer systemis an amount that is sufficient, when used with the remainingcomponents, to raise salivary pH to a pH of about 7.8 or more,preferably about 8.5 or more, and more preferably about 9 or more (e.g.,about 9-11), irrespective of the starting pH.

The two or more buffering agents are generally selected from a metaloxide, a citrate salt, a phosphate salt, a borate salt, an ascorbatesalt, an acetate salt, and alkaline starch. Suitable metal oxidesinclude, without limitation, magnesium oxide and aluminum oxide.Suitable citrate, phosphate, borate, ascorbate, and acetate saltsinclude, without limitation, essentially any salt of citric acid,phosphoric acid, boric acid, ascorbic acid, or acetic acid known in theart such as those described above. The amount of the additionalbuffering agents used in the buffer system is an amount that issufficient, when used with the carbonate salt or bicarbonate salt, toraise salivary pH to a pH of about 7.8 or more, preferably about 8.5 ormore, and more preferably about 9 or more (e.g., about 9-11),irrespective of the starting pH.

In certain instances, the buffer system comprises a carbonate salt or abicarbonate salt, a metal oxide, and a citrate, phosphate, or boratesalt. In certain other instances, the buffer system comprises acarbonate salt or a bicarbonate salt, a citrate salt, and a phosphatesalt. In certain instances, the buffer system comprises a carbonate saltor a bicarbonate salt, a citrate salt, and a borate salt. In certainother instances, the buffer system comprises a carbonate salt or abicarbonate salt, a phosphate salt, and a borate salt. Preferably, themetal oxide is amorphous magnesium oxide.

In certain instances, the amount of the carbonate salt or bicarbonatesalt in the buffer system is greater than or equal to the amount of themetal oxide or the citrate, phosphate, or borate salt. For example, theweight ratio of the carbonate salt or bicarbonate salt to the metaloxide or the citrate, phosphate, or borate salt can be from about 1:1 toabout 10:1, preferably from about 1:1 to about 5:1, and more preferablyfrom about 1:1 to about 3:1. In certain other instances, the amount ofthe carbonate salt or bicarbonate salt in the buffer system is less thanor equal to the amount of the metal oxide or the citrate, phosphate, orborate salt. For example, the weight ratio of the carbonate salt orbicarbonate salt to the metal oxide or the citrate, phosphate, or boratesalt can be from about 1:1 to about 1:10, preferably from about 1:1 toabout 1:5, and more preferably from about 1:1 to about 1:3.

While the foregoing discussion has focused on the ability of the buffersystem to alter salivary pH to favor substantial conversion to theun-ionized form of a therapeutic agent, it is conceivable that thebuffer system may also have subsidiary beneficial effects on the extentof absorption across the oral mucosa. For example, the buffer system maycreate a final salivary pH that in turn affects the molecularconfiguration of the therapeutic agent in a way in which absorptionacross the oral mucosa is increased. It is to be understood that thesesubsidiary beneficial effects of the buffer system are within thegeneral scope of the buffer system and compositions herein described.

C. Dosage Forms

The compositions of the present invention may take the form of solid,semi-solid, lyophilized powder, or liquid dosage forms, such as, forexample, tablets (e.g., chewable, slow-dissolving, quick-dissolving),pills, capsules, lozenges, gums, powders, solutions, suspensions,emulsions, aerosols, or the like. Preferably, the dosage form is achewing gum, dissolving tablet, chewable tablet, candy, or lozenge.

While each subject or patient possesses unique factors that may affectthe rate and extent of absorption of the therapeutic agents describedherein, dosage forms such as chewing gums, chewable tablets, dissolvingtablets, or lozenges containing a buffer system described herein offeradvantages over the traditional dosage forms for oral administration(i.e., Ambien®), For example, each of these dosage forms avoids hepaticfirst pass metabolism, degradation within the gastrointestinal tract,and drug loss during absorption. Consequently, the amount of therapeuticagent required per dose is less than that which would be required ifformulated, for example, in a pill or tablet for oral administration.Similarly, the bioavailability of the therapeutic agent is increased,thereby reducing the time to onset of therapeutic activity as comparedto traditional dosage forms for oral administration (see, Example 5below).

In addition, the preferred dosage forms of the present invention (e.g.,chewing gums, chewable tablets, dissolving tablets, lozenges) containinga buffer system described herein offer advantages over dosage forms fororal mucosal administration that do not contain the buffer system (i.e.,zolpidem FlashDose® tablet). Importantly, because the buffer system inthe dosage forms of the present invention helps convert substantiallyall of the therapeutic agent from its ionized form to its un-ionizedform, the bioavailability of the therapeutic agent is increased, therebyreducing the time to onset of therapeutic activity as compared to dosageforms for oral mucosal administration that do not contain the buffersystem. For example, U.S. Patent Publication No. 2003/0165566 disclosesthat the buccally administered zolpidem FlashDose® tablet has apharmacokinetic profile similar to that observed for the orallyadministered Ambien® tablet. As such, the zolpidem compositions of thepresent invention surpass both commercial tablet compositions byproviding an increase in the bioavailability of zolpidem and a reductionin the time to onset of therapeutic activity.

As used herein, the term “dosage form” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of therapeutic agentcalculated to produce the desired onset, tolerability, and therapeuticeffects, in association with one or more suitable pharmaceuticalexcipients such as carriers. Methods for preparing such dosage forms areknown or will be apparent to those skilled in the art. For example, insome embodiments, a chewing gum dosage form of the present invention canbe prepared according to the procedures set forth in U.S. Pat. No.4,405,647. In other embodiments, a tablet, lozenge, or candy dosage formof the present invention can be prepared according to the procedures setforth, for example, in Remington: The Science and Practice of Pharmacy,20^(th) Ed., Lippincott, Williams & Wilkins (2003); PharmaceuticalDosage Forms, Volume I: Tablets, 2^(nd) Ed., Marcel Dekker, Inc., NewYork, N.Y. (1989); and similar publications. The dosage form to beadministered will, in any event, contain a quantity of the therapeuticagent in a therapeutically effective amount for relief of the conditionbeing treated when administered in accordance with the teachings of thisinvention.

As used herein, the term “carrier” refers to a typically inert substanceused as a diluent or vehicle for a drug such as a therapeutic agent. Theterm also encompasses a typically inert substance that imparts cohesivequalities to the composition. Suitable carriers for use in thecompositions of the present invention include, without limitation, abinder, a gum base, and combinations thereof. Non-limiting examples ofbinders include mannitol, sorbitol, xylitol, maltodextrin, lactose,dextrose, sucrose, glucose, inositol, powdered sugar, molasses, starch,cellulose, microcrystalline cellulose, polyvinylpyrrolidone, acacia gum,guar gum, tragacanth gum, alginate, extract of Irish moss, panwar gum,ghatti gum, mucilage of isapol husks, Veegum®, larch arabogalactan,gelatin, methylcellulose, ethylcellulose, carboxymethylcellulose,hydroxypropylmethylcellulose, polyacrylic acid (e.g., Carbopol), calciumsilicate, calcium phosphate, dicalcium phosphate, calcium sulfate,kaolin, sodium chloride, polyethylene glycol, and combinations thereof.These binders can be pre-processed to improve their flowability andtaste by methods known in the art such as freeze drying (see, e.g.,Fundamentals of Freeze-Drying, Pharm. Biotechnol., 14:281-360 (2002);Lyophililization of Unit Dose Pharmaceutical Dosage Forms, Drug. Dev.Ind. Pharm., 29:595-602 (2003)); solid-solution preparation (see, e.g.,U.S. Pat. No. 6,264,987); and lubricant dusting and wet-granulationpreparation with a suitable lubricating agent (see, e.g., Remington: TheScience and Practice of Pharmacy, supra). For example, Mannogem® andSorbogem®, sold by SPI Pharma Group (New Castle, Del.), are freeze-driedprocessed forms of mannitol and sorbitol, respectively. Typically, thecompositions of the present invention comprise from about 25% to about90% by weight of the binder, and preferably from about 50% to about 80%.However, one skilled in the art will appreciate that the compositions ofthe present invention can be made without any binders, e.g., to producea highly friable dosage form.

Non-limiting examples of gum bases include materials selected from amongthe many water-insoluble and saliva-insoluble gum base materials knownin the art. For example, in some instances, the gum base comprises atleast one hydrophobic polymer and at least one hydrophilic polymer.Non-limiting examples of suitable hydrophobic and hydrophilic polymersfor gum bases include both natural and synthetic polymers such aselastomers, rubbers, and combinations thereof. Examples of suitablenatural polymers include, without limitation, substances of plant originsuch as chicle, jelutong, gutta percha, crown gum, and combinationsthereof. Examples of suitable synthetic polymers include elastomers suchas butadiene-styrene copolymers, isobutylene and isoprene copolymers(e.g., “butyl rubber”), polyethylene, polyisobutylene, polyvinylester(e.g., polyvinyl acetate and polyvinyl acetate phthalate), andcombinations thereof. In other instances, the gum base comprises amixture of butyl rubber (i.e., isobutylene and isoprene copolymer),polyisobutylene, and optionally, polyvinylacelate (i.e., having amolecular weight of approximately 12,000). Typically, the gum basecomprises from about 25% to about 75% by weight of these polymers, andpreferably from about 30% to about 60%.

The compositions of the present invention can additionally includelubricating agents; wetting agents; emulsifying agents; solubilizingagents; suspending agents; preserving agents such as methyl-, ethyl-,and propyl-hydroxy-benzoates, butylated hydrosytoluene, and butylatedhydroxyanisole; sweetening agents; flavoring agents; coloring agents;and disintegrating agents (i.e., dissolving agents) such as crospovidoneas well as croscarmellose sodium and other cross-linked cellulosepolymers.

Lubricating agents can be used to prevent adhesion of the dosage form tothe surface of the dies and punches, and to reduce inter-particlefriction. Lubricating agents may also facilitate ejection of the dosageform from the die cavity and improve the rate of granulation flow duringprocessing. Examples of suitable lubricating agents include, withoutlimitation, magnesium stearate, calcium stearate, zinc stearate, stearicacid, simethicone, silicon dioxide, talc, hydrogenated vegetable oil,polyethylene glycol, mineral oil, and combinations thereof. Thecompositions of the present invention can comprise from about 0% toabout 10% by weight of the lubricating agent, and preferably from about1% to about 5%.

Sweetening agents can be used to improve the palatability of thecomposition by masking any unpleasant tastes it may have. Examples ofsuitable sweetening agents include, without limitation, compoundsselected from the saccharide family such as the mono-, di-, tri-, poly-,and oligosaccharides; sugars such as sucrose, glucose (corn syrup),dextrose, invert sugar, fructose, maltodextrin, and polydextrose;saccharin and salts thereof such as sodium and calcium salts; cyclamicacid and salts thereof; dipeptide sweeteners; chlorinated sugarderivatives such as sucralose and dihydrochalcone; sugar alcohols suchas sorbitol, sorbitol syrup, mannitol, xylitol, hexa-resorcinol, and thelike, and combinations thereof. Hydrogenated starch, hydrolysate, andthe potassium, calcium, and sodium salts of3,6-dihydro-6-methyl-1-1,2,3-oxathiazin-4-one-2,3-dioxide may also beused. Of theforegoing, sorbitol, mannitol, and xylitol, either alone orin combination, are preferred sweetening agents. The compositions of thepresent invention can comprise from about 0% to about 80% by weight ofthe sweetening agent, preferably from about 5% to about 75%, and morepreferably from about 25% to about 50%.

Flavoring agents can also be used to improve the palatability of thecomposition. Examples of suitable flavoring agents include, withoutlimitation, natural and/or synthetic (i.e., artificial) compounds suchas peppermint, spearmint, wintergreen, cinnamon, menthol, cherry,strawberry, watermelon, grape, banana, peach, pineapple, apricot, pear,raspberry, lemon, grapefruit, orange, plum, apple, fruit punch, passionfruit, chocolate (e.g., white, milk, dark), vanilla, caramel, coffee,hazelnut, combinations thereof, and the like. Coloring agents can beused to color code the composition, for example, to indicate the typeand dosage of the therapeutic agent therein. Suitable coloring agentsinclude, without limitation, natural and/or artificial compounds such asFD & C coloring agents, natural juice concentrates, pigments such astitanium oxide, silicon dioxide, and zinc oxide, combinations thereof,and the like. The compositions of the present invention can comprisefrom about 0% to about 10% by weight of the flavoring and/or coloringagent, preferably from about 0.1% to about 5%, and more preferably fromabout 2% to about 3%.

1. Chewing Gums

When the dosage form is a chewing gum, the compositions of the presentinvention comprise a hypnotic agent or a pharmaceutically acceptablesalt thereof, a carrier such as a gum base, a binary or ternary buffersystem, and optionally a protecting agent. The chewing gum compositionmay further comprise lubricating agents, wetting agents, emulsifyingagents, solubilizing agents; suspending agents, preserving agents,sweetening agents, flavoring agents, and coloring agents. Typically, thechewing gum composition comprises from about 0.001% to about 10.0% byweight of the hypnotic agent (in whatever chosen form, measured as perits free base form), more typically from about 0.01% to about 5.0%, andstill more typically from about 0.1% to about 3.0%. One skilled in theart understands that the foregoing percentages will vary depending uponthe particular source of hypnotic agent utilized, the amount of hypnoticagent desired in the final formulation, as well as on the particularrelease rate of hypnotic agent desired. The binary or ternary buffersystem of the chewing gum composition provides for a final salivary pHin excess of at least about 7.8, preferably at least about 8.5, and morepreferably at least about 9 (e.g., about 9-11). The chewing gumcomposition typically comprises from about 20% to about 95% of the gumbase, more typically from about 30% to about 85%, and most typicallyfrom about 50% to about 70% of the gum base.

The chewing gum composition may further comprise a protecting agent. Theprotecting agent coats at least part of the therapeutic agent, typicallyupon the mixing of the two agents. The protecting agent may be mixedwith the therapeutic agent in a ratio of from about 0.1 to about 100 byweight, preferably in a ratio of from about 1 to about 50, and morepreferably in a ratio of about 1 to about 10. Without being bound to anyparticular theory, the protecting agent reduces the adhesion between thetherapeutic agent and the gum base so that the therapeutic agent may bemore easily released from the gum base. In this way, the therapeuticagent may be delivered across the mucous membranes of the oral cavitywithin about 5 to about 20 minutes of chewing, preferably within about10 minutes of chewing. A variety of different protecting agents may beused. Examples of suitable protecting agents include, withoutlimitation, calcium stearate, glycerin monostearate, glyceryl behenate,glyceryl palmitostearate, hydrogenated castor oil, hydrogenatedvegetable oil type I, light mineral oil, magnesium lauryl sulfate,magnesium stearate, mineral oil, poloxamer, polyethylene gycol, sodiumbenzoate, sodium chloride, sodium lauryl sulfate, stearic acid,cab-o-sil, talc, zinc stearate, and combinations thereof.

The gum base may additionally include plasticizers such as softeners oremulsifiers. Such plasticizers may, for example, help reduce theviscosity of the gum base to a desirable consistency and improve itsoverall texture and bite. Plasticizers may also facilitate the releaseof the therapeutic agent upon mastication. Non-limiting examples ofplasticizers include lecithin, mono- and diglycerides, lanolin, stearicacid, sodium stearate, potassium stearate, glycerol triacetate, glycerolmonostearate, glycerin, and combinations thereof. The gum base typicallycomprises from about 0% to about 20% by weight of the plasticizer, andmore typically from about 5% to about 15%.

The gum base may further comprise waxes such as beeswax andmicrocrystalline wax, fats or oils such as soybean and cottonseed oil,and combinations thereof. Typically, the gum base comprises from about0% to about 25% by weight of these waxes and oils, and more typicallycomprises from about 15% to about 20%.

In addition, the gum base may further comprise one or more elastomericsolvents such as rosins and resins. Non-limiting examples of suchsolvents include methyl, glycerol, and pentaerythritol esters of rosins,modified rosins such as hydrogenated, dimerized or polymerized rosins,or combinations thereof (e.g., pentaerythritol ester of partiallyhydrogenated wood rosin, pentaerythritol ester of wood rosin, glycerolester of wood rosin, glycerol ester of partially dimerized rosin,glycerol ester of polymerized rosin, glycerol ester of tall oil rosin,glycerol ester of wood rosin and partially hydrogenated wood rosin andpartially hydrogenated methyl ester of rosin such as polymers ofalpha-pinene or beta-pinene, terpene resins including polyterpene, andcombinations thereof). Typically, the gum base comprises from about 0%to about 75% of the elastomeric solvent, and more typically less thanabout 10%.

The gum base may further comprise a filler material to enhance thechewability of the final chewing gum composition. Fillers that aresubstantially non-reactive with other components of the final chewinggum formulation are preferable. Examples of suitable fillers include,without limitation, calcium carbonate, magnesium silicate (i.e., talc),dicalcium phosphate, metallic mineral salts (e.g., alumina, aluminumhydroxide, and aluminum silicates), and combinations thereof. Typically,the gum base comprises from about 0% to about 30% by weight of thefiller, and more typically from about 10% to about 20%.

One skilled in the art will appreciate that the gum base need not beprepared from its individual components. For example, the gum base canbe purchased with the desired ingredients contained therein, and can bemodified to include additional agents. Several manufacturers produce gumbases suitable for use with the described chewing gum compositions.Examples of such gum bases include, without limitation, Pharmagum™ M, S,or C (SFI Pharma Group; New Castle, Del.). In general, Pharmagum™comprises a mixture of gum base, sweetening agent, plasticizer, andsugar.

In certain instances, the chewing gum composition includes a therapeuticagent centerfill. A centerfill may be particularly suitable whenimmediate release of the therapeutic agent is preferred. In addition,encapsulating the therapeutic agent in a centerfill may help to mask anyundesirable taste that the therapeutic agent may have. In theseinstances, the gum base surrounds, at least in part, a centerfill. Thecenterfill comprises at least one therapeutic agent, and may be a liquidor semi-liquid material. The centerfill material can be a syntheticpolymer, a semi-synthetic polymer, low-fat, or fat-free and contain oneor more sweetening agents, flavoring agents, coloring agents, and/orscenting agents. Preferably, the centerfill includes a binary or ternarybuffer system as described herein. Methods for preparing a centerfillchewing gum are described, for example, in U.S. Pat. No. 3,806,290,which is hereby incorporated by reference in its entirety.

The chewing gum compositions can have any desired shape, size, andtexture. For example, the chewing gum can have the shape of a stick,tab, gumball, and the like. Similarly, the chewing gum can be anydesirable color. For example, the chewing gum can be any shade of red,blue, green, orange, yellow, violet, indigo, and mixtures thereof, andcan be color coded to indicate the type and dosage of the therapeuticagent therein. The chewing gum can be individually wrapped or groupedtogether in pieces for packaging by methods well known in the art.

2. Tablets

When the dosage form is a tablet such as a dissolving tablet (i.e.,disintegrating tablet) or chewable tablet, the compositions of thepresent invention comprise a hypnotic agent or a pharmaceuticallyacceptable salt thereof, a carrier such as a binder, and a binary orternary buffer system. The tablet composition may further compriselubricating agents, wetting agents, emulsifying agents, solubilizingagents; suspending agents, preserving agents, sweetening agents,flavoring agents, coloring agents, and disintegrating agents. Typically,the tablet compositions of the present invention comprise from about0.001% to about 10.0% by weight of the hypnotic agent (in whateverchosen form, measured as per its free base form), and more typicallyfrom about 1.0% to about 5.0%. In some embodiments, about 4.0% by weightof the hypnotic agent is used. One skilled in the art understands thatthe foregoing percentages will vary depending upon the particular sourceof hypnotic agent utilized, the amount of hypnotic agent desired in thefinal formulation, as well as on the particular release rale of hypnoticagent desired. The binary or ternary buffer system of the tabletcomposition provides for a final salivary pH in excess of at least about7.8, preferably at least about 8.5, and more preferably at least about 9(e.g., about 9-11).

In certain embodiments, the tablet is a dissolving tablet such as aslow-dissolving or quick-dissolving tablet that is dissolved by asubject's saliva, without the need for chewing. For example, adissolving tablet placed on the subject's tongue can be used for buccaldelivery of the therapeutic agent. Alternatively, a dissolving tabletplaced underneath the subject's tongue can be used for sublingualdelivery of the therapeutic agent. This type of dosage form may beparticularly desirable for pediatric and geriatric patients, since smallchildren and aged individuals often have difficulty chewing certainitem. Typically, the dissolving tablet is formulated to dissolve withinabout 1 to about 15 minutes, preferably within about 2 to about 10minutes, e.g., within about 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes,following administration. One skilled in the art will understand thatquick-dissolving tablets dissolve faster than slow-dissolving tablets,which are typically dissolved gradually rather than rapidly by asubject's saliva. In a preferred embodiment, the slow-dissolving orquick-dissolving tablet delivers the therapeutic agent across thesublingual mucosa.

In certain other embodiments, the tablet is a chewable tablet that ischewed by a subject and formulated to dissolve either rapidly orgradually. For example, a chewable tablet placed on the subject's tonguecan be used for buccal delivery of the therapeutic agent. Duringchewing, the chewable tablet can be moved around within the mouth andcan sometimes be parked between the gums and the cheeks or underneaththe tongue. As a result, at least a portion of the therapeutic agentcontained within a chewable tablet may also be delivered sublingually(i.e., across the sublingual mucosa). Typically, the chewable tablet isformulated to dissolve within about 1 to about 15 minutes, preferablywithin about 2 to about 10 minutes, e.g., within about 2, 3, 4, 5, 6, 7,8, 9, or 10 minutes, following administration.

As described, above, the dissolving and chewable tablets of the presentinvention are typically formulated to dissolve within about 1 to 15minutes following administration. However, while these time frames areamenable to maximum exposure of the therapeutic agent to the oral mucosa(e.g., to the sublingual and/or buccal mucosa), they are not alwaysamenable to user compliance (e.g., users may swallow 100 frequently and,therefore, hinder maximal transmucosal absorption). Consequently, incertain instances, it may be desirable to strike a balance betweenpatient compliance and maximum exposure time of the therapeutic agent tothe oral mucosa. This can be accomplished, for example, by reducing thetablet size (e.g., from about 700-800 mg to about 200-300 mg) withoutreducing the concentration or amount per unit dose of the buffer systemor the therapeutic agent. In addition, subtle changes to the tabletformulation such as, for example, replacing one flavoring agent foranother (e.g., chocolate for spearmint) or replacing one binder orsweetening agent for another (e.g., lactose for mannitol or sorbitol)may be used to reduce salivation.

The carrier present in the tablets of the present invention is typicallya binder that is useful in keeping the tablet in a semi-solid state, andmay be a solid or a liquid, and may for example be a high-melting pointfat or waxy material. Materials suitable as binders are discussed indetail above and may be used alone or in combination in the tabletcompositions of the present invention. In addition, binders such asmannitol, sorbitol, lactose, sucrose, and inositol can impart propertiesto the tablet that permit or enhance its disintegration in the mouth.

The tablet composition may further comprise a protecting agent. Theprotecting agent coats at least part of the therapeutic agent, typicallyupon the mixing of the two agents. The protecting agent may be mixedwith the therapeutic agent in a ratio of from about 0.1 to about 100 byweight, preferably in a ratio of from about 1 to about 50, and morepreferably in a ratio of about 1 to about 10. Without being bound to anyparticular theory, the protecting agent reduces the adhesion between thetherapeutic agent and the binder so that the therapeutic agent may bemore easily released from the binder. In this way, the therapeutic agentmay be delivered across the mucous membranes of the oral cavity withinabout 5 to about 20 minutes, preferably within about 10 minutes.Materials suitable as protecting agents are discussed in detail aboveand may be used alone or in combination in the tablet compositions ofthe present invention.

The tablet composition may also comprise one or more elastomericsolvents such as rosins and resins. Non-limiting examples of suchsolvents are discussed in detail above and may be used alone or incombination in the tablet compositions of the present invention. Inaddition, the tablet composition may further comprise waxes such asbeeswax and microcrystalline wax, fats or oils such as soybean andcottonseed oil, and combinations thereof. Moreover, the tabletcomposition may additionally include plasticizers such as softeners oremulsifiers. Such plasticizers may, for example, help reduce theviscosity of the salivary solution of the dissolved tablet to adesirable consistency and improve its overall texture and bite and helpfacilitate the release of the therapeutic agent. Non-limiting examplesof such plasticizers are discussed in detail above and may be used aloneor in combination in the tablet compositions of the present invention.

In certain instances, the tablet composition includes a therapeuticagent centerfill. A centerfill may be particularly suitable whenimmediate release of the therapeutic agent is preferred. In addition,encapsulating the therapeutic agent in a centerfill may help to mask anyundesirable taste that the therapeutic agent may have. In theseinstances, the binder surrounds, at least in part, a centerfill. Thecenterfill comprises at least one therapeutic agent, and may be a liquidor semi-liquid material. The centerfill material can be a syntheticpolymer, semi-synthetic polymer, low-fat, or fat-free and contain one ormore sweetening agents, flavoring agents, coloring agents, and/orscenting agents. Preferably, the centerfill includes a binary or ternarybuffer system as described herein.

In certain other instances, the tablet composition of the presentinvention is multilayered. In this way, the dissolving or chewabletablet can be designed to provide more than one therapeutic agent, e.g.,two or more hypnotic agents or one or more hypnotic agents incombination with one or more non-hypnotic therapeutic agents. Forexample, with a bi-layered tablet, the first layer contains a hypnoticagent and the second layer contains the same or different hypnotic agentor a non-hypnotic therapeutic agent. Typically, the first layercomprises the dissolving or chewable portion of the tablet, and thesecond (i.e., subsequent) layer is coated by the first layer. This typeof formulation may be particularly suitable when immediate release ofthe hypnotic agent, followed by gastrointestinal absorption of a secondtherapeutic agent, is desirable. Gastrointestinal absorption of thesecond therapeutic agent may be desirable, for example, in order tomitigate co-morbid symptoms or to sustain the therapeutic benefit of thehypnotic agent in the dissolving or the chewable portion of the tablet.Alternatively, the second layer is present as a layer lateral to thefirst layer. The second layer typically comprises at least onetherapeutic agent, and can also comprise one or more sweetening agents,flavoring agents, coloring agents, and scenting agents as describedabove. In some instances, the second layer further includes a binary orternary buffer system as described herein.

In still other instances, the combination of hypnotic agents with orwithout non-hypnotic therapeutic agents need not take the form of amultilayered tablet, but instead comprises a single homogenous tabletlayer. This type of formulation may also be used in the case wheregastrointestinal absorption of at least one therapeutic agent isdesirable. In this case, the relative extent of ionization of the two ormore therapeutic agents determines how they are to be absorbed. Forexample, those therapeutic agents that are un-ionized are absorbedthrough the oral mucosa, while the ionized agents are swallowed forgastrointestinal absorption.

The tablet compositions can have any desired shape, size, and texture.For example, the tablet can have the shape of a stick, tab, pellet,sphere, and the like. Similarly, the tablet can be any desirable color.For example, the tablet can be any shade of red, blue, green, orange,yellow, violet, indigo, and mixtures thereof, and can be color coded toindicate the type and dosage of the therapeutic agent therein. Thetablets can be individually wrapped or grouped together in pieces forpackaging by methods well known in the art.

3. Lozenges

When the dosage form is a lozenge or candy, the compositions of thepresent invention comprise a hypnotic agent or a pharmaceuticallyacceptable salt thereof, a carrier such as a binder, and a binary orternary buffer system. The lozenge or candy composition may furthercomprise lubricating agents, wetting agents, emulsifying agents,solubilizing agents; suspending agents, preserving agents, sweeteningagents, flavoring agents, coloring agents, and disintegrating agents. Ageneral discussion of lozenges and candies is provided, e.g., inPharmaceutical Dosage Forms, Volume 1: Tablets, 2^(nd) Ed., MarcelDekker, Inc., New York, N.Y., pages 75-418 (1989). Typically, thelozenge compositions of the present invention comprise from about 0.001%to about 10.0% by weight of the hypnotic agent (in whatever chosen form,measured as per its free base form), and more typically from about 1.0%to about 5.0%. In some embodiments, about 4.5% by weight of the hypnoticagent is used. One skilled in the art understands that the foregoingpercentages will vary depending upon the particular source of hypnoticagent utilized, the amount of hypnotic agert desired in the finalformulation, as well as on the particular release rate of hypnotic agentdesired. The binary or ternary buffer system of the lozenge compositionprovides for a final salivary pH in excess of at least about 7.8,preferably at least about 8.5, and more preferably at least about 9(e.g., about 9-11).

In certain embodiments, the lozenge or candy is dissolved by a subject'ssaliva, without the need for chewing. For example, a lozenge placed onthe subject's tongue can be used for buccal delivery of the therapeuticagent. Alternatively, a lozenge placed underneath the subject's tonguecan be used for sublingual delivery of the therapeutic agent. This typeof dosage form may be particularly desirable for pediatric and geriatricpatients, since small children and aged individuals often havedifficulty chewing certain items. Typically, the lozenge is formulatedto dissolve within about 1 to about 15 minutes, preferably within about2 to about 10 minutes, e.g., within about 2, 3, 4, 5, 6, 7, 8, 9, or 10minutes, following administration. In a preferred embodiment, thelozenge or candy delivers the therapeutic agent across the sublingualmucosa.

As described above, the lozenges the present invention are typicallyformulated to dissolve within about 1 to 15 minutes followingadministration. However, while these time frames are amenable to maximumexposure of the therapeutic agent to the oral mucosa (e.g., to thesublingual and/or buccal mucosa), they are not always amenable to usercompliance (e.g., users may swallow too frequently and, therefore,hinder maximal transmucosal absorption). Consequently, in certaininstances, it may be desirable to strike a balance between patientcompliance and maximum exposure time of the therapeutic agent to theoral mucosa. This can be accomplished, for example, by reducing thelozenge size (e.g., from about 700-800 mg to about 200-300 mg) withoutreducing the concentration or amount per unit dose of the buffer systemor the therapeutic agent. In addition, subtle changes to the lozengeformulation such as, for example, replacing one flavoring agent foranother (e.g., chocolate for spearmint) or replacing one binder orsweetening agent for another (e.g., lactose for mannitol or sorbitol)may be used to reduce salivation.

The carrier present in the lozenges of the present invention istypically a binder that is useful in keeping the lozenge in a semi-solidstate, and may be a solid or a liquid, and may for example be ahigh-melting point fat or waxy material. Materials suitable as bindersare discussed in detail above and may be used alone or in combination inthe lozenge compositions of the present invention. In addition, binderssuch as mannitol, sorbitol, lactose, sucrose, and inositol can impartproperties to the lozenge that permit or enhance its disintegration inthe mouth.

The lozenge composition may further comprise a protecting agent. Theprotecting agent coats at least part of the therapeutic agent, typicallyupon the mixing of the two agents. The protecting agent may be mixedwith the therapeutic agent in a ratio of from about 0.1 to about 100 byweight, preferably in a ratio of from about 1 to about 50, and morepreferably in a ratio of about 1 to about 10. Without being bound to anyparticular theory, the protecting agent reduces the adhesion between thetherapeutic agent and the binder so that the therapeutic agent may bemore easily released from the binder. In this way, the therapeutic agentmay be delivered across the mucous membranes of the oral cavity withinabout 5 to about 20 minutes, preferably within about 10 minutes.Materials suitable as protecting agents are discussed in detail above,and may be used alone or in combination in the lozenge compositions ofthe present invention.

The lozenge composition may also comprise one or more elastomericsolvents such as rosins and resins. Non-limiting examples of suchsolvents are discussed in detail above and may be used alone or incombination in the tablet compositions of the present invention. Inaddition, the lozenge composition may further comprise waxes such asbeeswax and microcrystalline wax, fats or oils such as soybean andcottonseed oil, and combinations thereof. Moreover, the lozengecomposition may additionally include plasticizers such as softeners oremulsifiers. Such plasticizers may, for example, help reduce theviscosity of the salivary solution of the dissolved lozenge to adesirable consistency and improve its overall texture and bite and helpfacilitate the release of the therapeutic agent. Non-limiting examplesof such plasticizers are discussed in detail above and may be used aloneor in combination in the lozenge compositions of the present invention.

In certain instances, the lozenge composition includes a therapeuticagent centerfill. A centerfill may be particularly suitable whenimmediate release of the therapeutic agent is preferred. In addition,encapsulating the therapeutic agent in a centerfill may help to mask anyundesirable taste that the therapeutic agent may have. In theseinstances, the binder surrounds, at least in part, centerfill. Thecenterfill comprises at least one therapeutic agent, and may be a liquidor semi-liquid material. The centerfill material can be low-fat or fatfree and contain one or more sweetening agents, flavoring agents,coloring agents, and/or scenting agents. Preferably, the centerfillincludes a binary or ternary buffer system as described herein.

In certain other instances, the lozenge composition of the presentinvention is multilayered. In this way, the lozenge can be designed toprovide more than one therapeutic agent, e.g., two or more hypnoticagents or one or more hypnotic agents in combination with one or morenon-hypnotic therapeutic agents. For example, with a bi-layered lozenge,the first layer contains a hypnotic agent and the second layer containsthe same or different hypnotic agent or a non-hypnotic therapeuticagent. Typically, the first layer comprises the dissolving portion ofthe lozenge, and the second (i.e., subsequent) layer is coated by thefirst layer. This type of formulation may be particularly suitable whenimmediate release of the hypnotic agent, followed by gastrointestinalabsorption of a second therapeutic agent, is desirable. Gastrointestinalabsorption of the second therapeutic agent may be desirable, forexample, in order to mitigate co-morbid symptoms or to sustain thetherapeutic benefit of the hypnotic agent in the dissolving portion ofthe lozenge. Alternatively, the second layer is present as a layerlateral to the first layer. The second layer typically comprises atleast one therapeutic agent, and can also comprise one or moresweetening agents, flavoring agents, coloring agents, and scentingagents as described above. In some instances, the second layer furtherincludes a binary or ternary buffer system as described herein.

In still other instances, the combination of hypnotic agents with orwithout non-hypnotic therapeutic agents need not take the form of amultilayered lozenge, but instead comprises a single homogenous lozengelayer. This type of formulation may also be used in the case wheregastrointestinal absorption of at least one therapeutic agent isdesirable. In this case, the relative extent of ionization of the two ormore therapeutic agents determines how they are to be absorbed. Forexample, those therapeutic agents that are un-ionized are absorbedthrough the oral mucosa, while the ionized agents are swallowed forgastrointestinal absorption.

The lozenge compositions can have any desired shape, size, and texture.For example, the lozenge can have the shape of a stick, tab, pellet,sphere, and the like. Similarly, the lozenge can be any desirable color.For example, the lozenge can be any shade of red, blue, green, orange,yellow, violet, indigo, and mixtures thereof, and can be color coded toindicate the type and dosage of the therapeutic agent therein. Thelozenges can be individually wrapped or grouped together in pieces forpackaging by methods well known in the art.

D. Methods of Administration

The compositions of the present invention are useful in therapeuticapplications, e.g., for treating a sleep disorder. Importantly, thecompositions of the present invention provide the rapid and predictabledelivery or a hypnotic agent across the oral mucosa with surprisinglylow inter-subject variability in terms of maximum plasma concentration(C_(max)) and the time to reach the maximum plasma concentration(T_(max)) by raising the pH of saliva to a pH greater than about 7.8,irrespective of the starting pH of saliva. In particular, the deliveryof the therapeutic agent across the oral mucosa avoids hepatic firstpass metabolism, degradation within the gastrointestinal tract, and drugloss during absorption. As a result, the therapeutic agent reaches thesystemic circulation in a substantially shorter period of time and at asubstantially higher concentration than with traditional oral (e.g.,tablet) administration.

In addition, the compositions of the present invention offer advantagesover compositions for oral mucosal administration that do not containthe buffer system described herein. In particular, because the buffersystem in the compositions of the present invention helps convertsubstantially all of the therapeutic agent from its ionized form to itsun-ionized form, the therapeutic agent reaches the systemic circulationin a substantially shorter period of time (e.g., reducing the time toonset of therapeutic activity) and at a substantially higherconcentration than with compositions for oral mucosal administrationthat do not contain the buffer system.

The compositions of the present invention have particular utility in thearea of human and veterinary therapeutics. Generally, administereddosages will be effective to deliver picomolar to micromolarconcentrations of the hypnotic agent to the appropriate site.

Administration of the compositions of the present invention ispreferably carried out via any of the accepted modes of administrationto the mucous membranes of the oral cavity. Examples of suitable sitesof administration within the oral mucosa include, without limitation,the mucous membranes of the floor of the mouth (sublingual mucosa), thecheeks (buccal mucosa), the gums (gingival mucosa), the roof of themouth (palatal mucosa), the lining of the lips, and combinationsthereof. These regions differ from each other with respect to theiranatomy, drug permeability, and physiological response to drugs.Preferably, the compositions of the present invention are administeredto the sublingual mucosa, buccal mucosa, or a combination thereof.

The oral mucosa, possessing a rich blood supply and suitable drugpermeability, is an especially attractive route of administration forsystemic drug delivery. Furthermore, delivery of a therapeutic agentacross the oral mucosa bypasses hepatic first pass metabolism, avoidsenzymatic degradation within the gastrointestinal tract, and provides amore suitable enzymatic flora for drug absorption. As used herein, theterm “sublingual delivery” refers to the administration of a therapeuticagent across the mucous membranes lining the floor of the mouth and/orthe ventral tongue. The term “buccal delivery” as used herein refers tothe administration of a therapeutic agent across the mucous membraneslining the cheeks.

The oral mucosa is composed of an outermost layer of stratified squamousepithelium. Beneath this layer lies a basement membrane, i.e., thelamina propria, followed by the submucosa as the innermost layer. Theepithelium of the oral mucosa is similar to the stratified squamousepithelia found in the rest of the body in that it contains amitotically active basal cell layer, advancing through a number ofdifferentiating intermediate layers to the superficial layers, wherecells are shed from the surface of the epithelium (Gandhi et al., Ind.J. Pharm. Sci., 50:145-152 (1988)). For example, the epithelium of thebuccal mucosa is about 40-50 cell layers thick, while that of thesublingual epithelium contains somewhat fewer cell layers. Theepithelial cells increase in size and become flatter as they travel fromthe basal layers to the superficial layers.

The turnover time for buccal mucosal epithelium, estimated at 5-6 days,is representative of the turnover time for sublingual mucosal epitheliumas well as other epithelia in the oral mucosa (Harris et al., J. Pharm.Sci., 81:1-10 (1992)). The thickness of the oral mucosa varies dependingon the site in the oral cavity. For example, the buccal mucosa measuresat about 500-800 μm in thickness, while the hard and soft palatalmucosa, the sublingual mucosa, the ventral tongue, and the gingivalmucosa measure at about 100-200 μm in thickness. The composition of theepithelium also varies depending on the site in the oral cavity. Forexample, the mucosae of areas subject to mechanical stress (i.e., thegingivae and hard palate) are keratinized similar to the epidermis.However, the mucosae of the soft palate, the sublingual region, and thebuccal region are not keratinized (Harris et a., supra). The keratinizedepithelia contain neutral lipids like ceramides and acylceramides, whichhave been associated with providing a barrier function. As a result,these epithelia are relatively impermeable to water. In contrast,non-keratinized epithelia, such as sublingual and buccal epithelia, donot contain acylceramides and have only small amounts of ceramide (Wertzet al., Crit. Rev. Ther. Drug Carr. Sys., 8:237-269 (1991); Squier etal., J. Invest. Dermat., 90:123-126 (1991); Squier et al., in OralMucosal Drug Delivery, Ed. M. J. Rathbone, Marcel Dekker, Inc., NewYork, N.Y., 1-26 (1996)). Non-keratinized epithelia also contain smaltamounts of neutral but polar lipids, e.g., cholesterol sulfate andglucosyl ceramides. As such, these epithelia have been found to beconsiderably more permeable to water than keratinized epithelia (Harriset al., supra; Wertz et al., supra; Squier et al., supra 1991).

In general, the oral mucosa is a somewhat leaky epithelia intermediatebetween that of the epidermis and intestinal mucosa. For example, thepermeability of the buccal mucosa is estimated to be about 4-4000 timesgreater than that of skin (Galey et al., J. Invest. Dermat., 67:713-717(1976)). The permeability of different regions of the oral mucosagenerally decrease in the order of sublingual mucosa greater than buccalmucosa, and buccal mucosa greater than palatal mucosa (Harris et al.,supra). This permeability is generally based upon the relative thicknessand degree of keratinization of these membranes, with the sublingualmucosa being relatively thin and non-keratinized, the buccal mucosabeing thicker and non-keratinized, and the palatal mucosa beingintermediate in thickness, but keratinized.

The epithelial cells of the oral mucosa are surrounded by mucuscomprising primarily complexes of proteins and carbohydrates that may ormay not be attached to certain regions on the cell surface. The mucusmay play a role in cell-cell adhesion, as well as acting as a lubricant,allowing cells to move relative to one another (Tabak et al., J. OralPathol., 11:1-17 (1982)). In stratified squamous epithelia foundelsewhere in the body, mucus is synthesized by specialized mucussecreting cells such as goblet cells; however, in the oral mucosa, mucusis secreted by the major and minor salivary glands as part of saliva(Tabak et al., supra; Rathbone et al., Adv. Drug Del. Rev., 13:1-22(1994)). At physiological pH, the mucus network carries a negativecharge due to the sialic acid and sulfate residues present on thecarbohydrates. At this pH, mucus can form a strongly cohesive gelstructure that binds to the epithelial cell surface as a gelatinouslayer (Gandhi et al., supra). Without being bound to any particulartheory, the buffer systems of the present invention neutralize thesialic acid residues present on the carbohydrates and prevent them frominteracting with the therapeutic agent, thereby further enhancing drugpermeation.

Another feature of the environment of the oral cavity is the presence ofsaliva produced by the salivary glands. Saliva is the protective fluidfor all tissues of the oral cavity. Saliva is an aqueous fluid withabout 1% organic and inorganic materials. The major determinant of thesalivary composition is the flow rate, which in turn depends uponfactors such as the time of day, the type of stimulus, and the degree ofstimulation. The salivary pH typically ranges from about 5.5 to about7.0, depending on the flow rate. For example, at high flow rates, thesodium and bicarbonate concentrations increase, leading to an increasein the pH. Because the daily salivary volume is between about 0.5 toabout 2 liters, the oral cavity provides an aqueous environment for thehydration and/or dissolution of the oral mucosal dosage forms of thepresent invention.

The sublingual mucosa is the most highly permeable region of the oralcavity, and provides rapid absorption and high bioavailability of a drugin a convenient, accessible, and well-accepted route of administration(Harris et al., supra). Suitable sublingual dosage forms include,without limitation, tablets (e.g., quick-dissolving, slow-dissolving),lozenges, candy, and soft gelatin capsules filled with liquid drug. Suchsystems create a very high drug concentration in the sublingual regionbefore they are systemically absorbed across the sublingual mucosa. As aresult, the sublingual mucosa is particularly well-suited for producinga rapid onset of action, and sublingual dosage forms can be used todeliver drugs with shorter delivery period requirements and/or lessfrequent dosing regimens. Although the buccal mucosa is considerablyless permeable than the sublingual area, rapid absorption and highbioavailability of a drug can also be observed with buccaladministration. Suitable buccal dosage forms include, withoutlimitation, chewing gums, tablets (e.g., quick-dissolving,slow-dissolving), lozenges, candy, and the like. Both the buccal mucosaand the sublingual mucosa are far superior to the gastrointestinal tractfor providing increased absorption and bioavailability of a drug.

To increase the permeability of drugs through the oral mucosa,penetration enhancers can be included in the dosage forms of the presentinvention. The penetration enhancers may be of the type that alters thenature of the oral mucosa to enhance penetration, or of the type thatalters the nature of the therapeutic agent to enhance penetrationthrough the oral mucosa. Suitable penetration enhancers include, withoutlimitation, polyoxyethylene 23-lauryl ether, aprotin, azone,benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammoniumbromide, cyclodextrin, dextran sulfate, lauric acid, propylene glycol,lysophosphatidylcholine, menthol, methoxysalicylate, methyloleate, oleicacid, phosphatidylcholine, polyoxyethylene, polysorbate 80, sodiumethylenediaminetetraacetic acid (“EDTA”), sodium deoxycholate, sodiumglycocholate, sodium glycodeoxycholate, sodium lauryl suflate, sodiumsalicylate, sodium taurocholate, sodium taurodeoxycholate, as well ascertain sulfoxides and glycosides, and combinations thereof.

IV. Examples

The following examples are offered to illustrate, but not to limit, theclaimed invention.

Example 1 Zolpidem Membrane Assay

This example illustrates the beneficial effects of pH adjustment onmembrane penetration for a zolpidem dosage form.

The effect of pH adjustment on the extent of ionization, and hence, theextent to which a therapeutic agent will traverse the mucous membranecan be demonstrated using a membrane assay; see, e.g., Kansy et al., J.Med. Chem., 41:1007-1010 (1998); and Avdeel, Curr. Topics Med. Chem.,1:277-351 (2001). This assay uses a lipid-coated membrane to predictlipid mucosal membrane penetration. The membrane apparatus consists of adodecane membrane sandwiched between a donor and acceptor cell. Thelipid-coated membrane is less porous then the mucous membrane of theoral cavity. Thus, the enhancement seen in the membrane assay is verylikely to be magnified in vivo.

Membrane assays were performed using zolpidem tartrate solutions at a pHof 5.8, 6.8, and 7.8. The alkaline pH values of 7.8 were adjusted usingfreshly prepared 0.01 M sodium bicarbonate/sodium carbonate buffersolution. The acidic pH of 5.8 was achieved using a 0.01 M acetatebuffer solution (a mixture of sodium acetate and acetic acid). Theneutral pH of 6.8 was achieved by adding 0.01 M acetate solution to thesodium bicarbonate/sodium carbonate buffer solution. Permeation throughthe membrane was measured by determining the concentration of zolpidemin the acceptor cell and is expressed as P_(c) (effective permeabilityin centimeters per second). As shown in Table 1 below, the effectivepermeability of zolpidem increased by more than 53% at a pH of 7.8relative to a pH of 6.8 and 129% relative to a pH of 5.8. FIG. 1 shows abar chart illustrating the relationship between pH and zolpidem membranepermeability.

TABLE 2 Zolpidem slow-dissolving tablet formulation. Material UnitQuantity (mg) Batch Quantity (g) Sodium Carbonate, NF 17.000 357.000Sodium Bicarbonate USP 23.000 483.000 Zolpidem Tartrate, EP 10.000210.000 Mannitol, USP 40.000 840.000 Sorbitol, NF 136.000 2856.000Natural & Artificial Spearmint 6.500 136.500 Flavor Sucralose, NF 1.00021.000 Silicon Dioxide, USP 5.500 115.500 Stearic Acid, NF 3.500 73.500Magnesium Stearate, NF 7.500 157.500 The batch quantity formulationproduces 21,000 unit doses.

Example 2 Zolpidem Gum Compositions

This example illustrates the zolpidem chewing gum compositions of thepresent invention.

Zolpidem can be formulated as a chewing gum composition as describedabove. In these embodiments, the unit dose or serving of the chewing gumcomprises from about 0.1 to about 100 milligrams (mg) zolpidem (asmeasured in its tartrate salt form), preferably from about 1 to about 50mg, and more preferably from about 2 to about 25 mg. In otherembodiments, the unit dose comprises from about 2 to about 20 mgzolpidem, preferably from about 5 to about 15 mg. Extra zolpidem, forexample, up to from about 10% to about 25% by weight, can be added as“overage” or as the amount that may be expected to be “washed away” andnot otherwise released or absorbed during mastication.

In another embodiment, the unit dose or serving of the chewing gumcomprises from about 0.81 to about 42 mg zolpidem in its base form, andmore preferably from about 1.64 to about 20.5 mg. In other embodiments,the unit dose comprises from about 1.64 to about 16.4 mg zolpidem in itsfree base form, preferably from about 1.64 to about 12.3 mg, and morepreferably from about 1.64 to about 8.2 mg, e.g., about 1.84, 2.46,3.28, 4.1, 4.92, 5.78, 6.56, 7.38, or 8.2 mg. In additional embodiments,the unit dose comprises a mixture of zolpidem in free base form and saltform (e.g., zolpidem tartrate).

Given in weight percentages, the zolpidem chewing gum compositioncomprises from about 0.001% to about 10.0% zolpidem (in whatever chosenform, measured as per its free base form), preferably from about 0.05%to about 2.0%, and more preferably from about 0.1% to about 1.0%. Insome embodiments, about 0.25% zolpidem is used. One skilled in the artunderstands that the foregoing percentages will vary depending upon theparticular source of zolpidem utilized, the amount of zolpidem desiredin the final formulation, as well as on the particular release rate ofzolpidem desired. The buffer system of the zolpidem chewing gumcomposition provides for a final salivary pH in excess of at least about7.8, preferably at least about 8.5, and more preferably at least about 9(e.g., about 9-11).

A zolpidem chewing gum was made according to the following procedure.Silicon dioxide USP (0.35 kg) was passed through a #20 mesh screen, andthen loaded into a blender containing 0.810 kg mannitol granular USP and9.569 kg Pharmagum™ C. The material was blended for 10 minutes. Zolpidemtartrate EP (0.034 kg) was ground with the silicon dioxide (0.02 kg)using a mortar and pestle. The remaining silicon dioxide, along with0.228 kg magnesium stearate, was added into the mortar while continuingto grind. The ground materials were transferred into a plastic bag, andthe mortar was rinsed using 0.01 kg silicone dioxide, and transferredinto the bag. The contents of the bag were then blended for fiveminutes.

Equal parts of the blended bag contents and the blended mannitol gumbase mixture were blended for an additional five minutes. This processwas repeated until all the zolpidem and gum base mixture had beenblended together. Sodium carbonate (0.110 kg), sodium bicarbonate (0.570kg), gum acacia (0.43 kg), xanthan gum (0.013 kg), and aspartame (0.072kg) were then loaded into the blender along with natural and artificialflavors and blended for ten minutes with 0.090 kg of silicon dioxide.The flavors used were as follows: natural and artificial grape flavorS.D. (0.215 kg), natural and artificial cherry flavor (0.108 kg),natural and artificial fruit punch flavor S.D. (0.180 kg), naturalcherry WONF DURAROME® flavor (0.215 kg), and natural passion fruit typeDURAROME® flavor (0.035 kg).

The blend was passed through a #12 mesh screen and then blended for anadditional 15 minutes. Magnesium stearate (0.114 kg) was passed througha #20 mesh screen and added to the blend and blended for five minutes.The blend was collected and placed in plastic bags. Two silica geldesiccant bags were placed around the plastic bags to absorb ambientmoisture. The blend was then compressed into tablets. By using theabove-described procedure, the average particle size of the drug (i.e.,zolpidem) in the chewing gum is about 20 microns, as compared to atypical average drug particle size of from about 75 to about 100microns. In addition, the average particle size of the drug in thechewing gum is less than or equal to the average particle size of thecarrier ingredients (e.g., gum base, binders, etc.).

The zolpidem chewing gum composition of the present invention can beused, e.g., for treatment of insomnia; see, Holm et al., Drugs,59:865-889 (2000). In certain instances, after the introduction of aserving size piece of the chewing gum composition into the mouth, thesubject chews the chewing gum as is normally done with any non-medicatedtype of chewing gum for about 5 to about 20 minutes, at approximately anaverage rate of about 10 to about 45 chews per minute. The gum is thendiscarded.

A typical dosage form of the zolpidem chewing gum of the presentinvention is designed to produce an average plasma concentration of atleast from about 20 to about 300 nanograms of zolpidem per milliliter ofplasma. For example, a 5 mg zolpidem chewing gum can be designed toproduce a mean peak plasma concentration within the range of from about20 to about 100 nanograms of zolpidem per milliliter of plasma withinabout 5 minutes to about 2 hours. Similarly, a 10 mg zolpidem chewinggum can be designed to produce a mean peak plasma concentration withinthe range of from about 100 to about 300 nanograms of zolpidem permilliliter of plasma within about 5 minutes to about 2 hours.

The chewing gum compositions of the present invention provide aconvenient, reliable, practical, and painless system for deliveringzolpidem across the oral mucosa. Notably, the chewing gum compositionsare capable of rapidly delivering zolpidem with low inter-subjectvariability in terms of maximum plasma concentration (C_(max)) and thetime to reach the maximum plasma concentration (T_(max)) so that atherapeutically effective amount of zolpidem enters the bloodstreamwithin about 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes,or even within about 1-2 minutes after zolpidem is released from thecarrier.

Example 3 Zolpidem Tablet Compositions

This example illustrates the slow-dissolving, quick-dissolving, andchewable zolpidem tablet compositions of the present invention.

Zolpidem can be formulated as a tablet composition as described above.In these embodiments, the unit dose or serving of the tablet comprisesfrom about 0.1 to about 100 milligrams (mg) zolpidem (as measured in itstartrate salt form), preferably from about 1 to about 50 mg, and morepreferably from about 2 to about 25 mg. In other embodiments, the unitdose comprises from about 2 to about 20 mg zolpidem, preferably fromabout 2 to about 15 mg, and more preferably from about 2 to about 10 mg,e.g., about 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg. In particularly preferredembodiments, the unit dose comprises a dose of zolpidem that is lessthan the dose typically used in commercial oral tablets, but possessescomparable or greater bioavailability and onset of therapeutic activityas well as lower variability of drug absorption. In such embodiments,unit doses of from about 2 to about 5 mg zolpidem are preferred, withunit doses of about 4 mg zolpidem being particularly preferred. Extrazolpidem, for example, up to from about 10% to about 25% by weight, canbe added as “overage” or as the amount that may be expected to be“washed away” and not otherwise released or absorbed during tabletdissolution and/or mastication.

In another embodiment, the unit dose or serving of the tablet comprisesfrom about 0.81 to about 42 mg zolpidem in its base form, and morepreferably from about 1.64 to about 20.5 mg. In other embodiments, theunit dose comprises from about 1.64 to about 16.4 mg zolpidem in itsfree base form, preferably from about 1.64 to about 12.3 mg, and morepreferably from about 1.64 to about 8.2 mg, e.g., about 1.64, 2.46,3.28, 4.1, 4.92, 5.78, 6.56, 7.38, or 8.2 mg. In additional embodiments,the unit dose comprises a mixture of zolpidem in free base form and saltform (e.g., zolpidem tartrate).

Given in weight percentages, the zolpidem tablet composition comprisesfrom about 0.001% to about 10.0% zolpidem (in whatever chosen form,measured as per its free base form), preferably from about 0.1% to about8.0%, more preferably from about 1.0% to about 7.0%, and still morepreferably from about 1.0% to about 5.0%. In some embodiments, about4.0% zolpidem is used. One skilled in the art understands that theforegoing percentages will vary depending upon the particular source ofzolpidem utilized, tbe amount of zolpidem desired in the finalformulation, as well as on the particular release rate of zolpidemdesired. The buffer system of the zolpidem tablet composition providesfor a final salivary pH in excess of at least about 7.8, preferably atleast about 8.5, and more preferably at least about 9 (e.g., about9-11).

Zolpidem Slow-Dissolving Tablets:

A zolpidem slow-dissolving tablet was made according to the followingprocedure. Magnesium stearate USP (0.35 kg) was passed through a #20mesh screen, and then loaded into a blender containing 0.810 kg mannitolgranular USP and 9.569 kg sorbitol. The material was blended for 10minutes. Zolpidem tartrate EP (0.034 kg) was ground with the magnesiumstearate (0.02 kg) using a mortar and pestle. The remaining silicondioxide, along with 0.228 kg magnesium stearate was added into themortar while continuing to grind. The ground materials were transferredinto a plastic bag, and the mortar was rinsed using 0.01 kg siliconedioxide, and transferred into the bag. The contents of the bag were thenblended for five minutes.

Equal parts of the blended bag contents and the blended mannitol mixturewere blended for an additional five minutes. This process was repeateduntil all the zolpidem and mannitol mixture had been blended together.Sodium carbonate (0.110 kg), sodium bicarbonate (0.570 kg), gum acacia(0.43 kg), xanthan gum (0.013 kg), and aspartame (0.072 kg) were thenloaded into the blender with natural and artificial flavors and blendedfor ten minutes with 0.090 kg of silicon dioxide. The flavors used wereas follows: natural and artificial grape flavor S.D. (0.215 kg), naturaland artificial cherry flavor (0.108 kg), natural and artificial fruitpunch flavor S.D. (0.180 kg), natural cherry WONF DURAROME® flavor(0.215 kg), and natural passion fruit type DURAROME® flavor (0.035 kg).

The blend was passed through a #12 mesh screen and then blended for anadditional 15 minutes. Magnesium stearate (0.114 kg) was passed througha #20 mesh screen and added to the blend and blended for five minutes.The blend was collected and placed in plastic bags. Two silica geldssiccant bags were placed around the plastic bags to absorb ambientmoisture. The blend was then compressed into tablets. By using thisprocedure, the average particle size of the drug (i.e., zolpidem) in theslow-dissolving tablet is about 20 microns, as compared to a typicalaverage drug particle size of from about 75 to about 100 microns. Inaddition, the average particle size of the drug in the slow-dissolvingtablet is less than or equal to the average particle size of the carrieringredients (e.g., gum base, binders, etc.).

A second zolpidem slow-dissolving tablet was made according to theformulation shown in Table 2 and the following procedure. Three separateblends of silicon dioxide with zolpidem, sodium bicarbonate, and sodiumcarbonate; mannitol and sorbitol; and spearmint flavor, sucralose,stearic acid, and magnesium stearate were prepared. The three blendswere screened separately and mixed to form a single blend. The singleblend was then compressed into tablets after testing for contentuniformity. By using this procedure, the average particle size of thedrug (i.e., zolpidem) in the slow-dissolving tablet is about 20 microns,which is less than or equal to the average particle size of the carrieringredients (e.g., gum base, binders, etc.). The unit weight for eachtablet was 250 mg. The pH of the tablet was about 9.8 and remainedstable. These tablets dissolve within about 10 minutes followingsublingual administration.

TABLE 2 Zolpidem slow-dissolving tablet formulation. Material UntiQuantity (mg) Batch Quantity (g) Sodium Carbonate, NF 17.000 357.000Sodium Bicarbonate 23.000 483.000 Zolpidem Tartrate, EP 10.000 210.000Mannitolm USP 40.000 840.000 Sorbitol, NF 136.000 2856.000 Natural &Artificial 6.500 136.500 Spearmint Flavor Sucralose, NF 1.000 21.000Silicon Dioxide, USP 5.500 115.500 Stearic Acid, NF 3.500 73.500Magnesium Stearate, NF 7.500 157.500 The batch quantity formulationproduces 21,000 unit doses.

Zolpidem Quick-Dissoving Tablets:

A zolpidem quick-dissolving tablet was made according to the followingprocedure. Mannitol (3.633 kg) and sorbitol (0.469 kg) were blended forten minutes. Sodium carbonate (0.330 kg), sodium bicarbonate (0.165 kg),natural peppermint flavor (0.125 kg), natural menthol flavor (0.025 kg),and sucralose (0.020 kg) were blended separately for ten minutes.Magnesium stearate (0.075 kg), and zolpidem tartrate (0.034 kg) wereblended for ten minutes and then passed through a #12 mesh screen. Theblended mixtures were then added together and compressed into tablets.By using this procedure, the average particle size of the drug (i.e.,zolpidem) in the quick-dissolving tablet is about 20 microns, ascompared to a typical average drug particle size of from about 75 toabout 100 microns. In addition, the average particle size of the drug inthe quick-dissolving tablet is less than or equal to the averageparticle size of the carrier ingredients (e.g., gum base, binders,etc.).

A second zolpidem quick-dissolving tablet was made according to theformulation shown in Table 3 and the following procedure. Three separateblends of silicon dioxide with zolpidem, sodium carbonate, and sodiumbicarbonate; mannitol and sorbitol; and polyethylene glycol, spearmintflavor, sucralose, magnesium stearate, crospovidone, and croscarmellosesodium were prepared. The three blends were screened separately andmixed to form a single blend. The single blend was then compressed intotablets after testing for content uniformity. By using this procedure,the average particle size of the drug (i.e., zolpidem) in thequick-dissolving tablet is about 20 microns, which is less than or equalto the average particle size of the carrier ingredients (e.g., gum base,binders, etc.). The unit weight for each tablet was 250 mg. The pH ofthe tablet was about 9.8 and remained stable. These tablets dissolvewithin about 5 minutes following sublingual administration.

TABLE 3 Zolpidem quick-dissolving tablet formulation. Material UnitQuantity (mg) Batch Quantity (g) Sodium Carbonate, NF 17.000 357.000Sodium Bicarbonate USP 23.000 483.000 Zolpidem Tartrate, EP 10.000210.000 Mannitol, USP 40.000 840.000 Sorbitol, NF 103.500 2173.500Crospovidone, NF 12.500 262.500 Croscarmellose Sodium, NF 12.500 262.500Polyethylene Glycol 3350, NF 12.500 262.500 Natural & ArtificialSpearmint 6.500 136.500 Flavor Sucralose, NF 1.000 21.000 SiliconDioxide, USP 8.500 178.500 Magnesium Stearate, NF 3.000 63.000 The batchquantity formulation produces 21,000 unit doses.

Zolpidem Chewable Tablets:

A zolpidem chewable tablet was made according to the followingprocedure. Magnesium stearate USP (0.35 kg) was passed through a #20)mesh screen, and then loaded into a blender containing 0.810 kg mannitolgranular USP, 9.569 kg sorbitol, and 0.020 kg stearic acid. The materialwas blended for 10 minutes. Zolpidem tartrate EP (0.034 kg) was groundwith the magnesium stearate (0.02 kg) using a mortar and pestle. Theremaining silicon dioxide, along with 0.228 kg magnesium stearate wasadded into the mortar while continuing to grind. The ground materialswere transferred into a plastic bag, and the mortar was rinsed using0.01 kg silicone dioxide, and transferred into the bag. The contents ofthe bag were then blended for five minutes.

Equal parts of the blended bag contents and the blended mannitol mixturewere blended for an additional five minutes. This process was repeateduntil all the zolpidem and mannitol mixture had been blended together.Sodium carbonate (0.110 kg), sodium bicarbonate (0.570 kg), gum acacia(0.43 kg), xanthan gum (0.013 kg), and aspartame (0.072 kg) were thenloaded into the blender with natural and artificial flavors and blendedfor ten minutes with 0.090 kg of silicon dioxide. The flavors used wereas follows: natural and artificial grape flavor S.D. (0.215 kg), naturaland artificial cherry flavor (0.108 kg), natural and artificial fruitpunch flavor S.D. (0.180 kg), natural cherry WONF DURAROME® flavor(0.215 kg), and natural passion fruit type DURAROME® flavor (0.035 kg).

The blend was passed through a #12 mesh screen and then blended for anadditional 15 minutes. Magnesium stearate (0.114 kg) was passed througha #20 mesh screen and added to the blend and blended for five minutes.The blend was collected and placed in plastic bags. Two silica geldesiccant bags were placed around the plastic bags to absorb ambientmoisture. The blend was then compressed into tablets. By using thisprocedure, the average particle size of the drug (i.e., zolpidem) in thechewable tablet is about 20 microns, as compared to a typical averagedrug particle size of from about 75 to about 100 microns. In addition,the average particle size of the drug in the chewable tablet is lessthan or equal to the average particle size of the carrier ingredients(e.g., gum base, binders, etc.).

The zolpidem tablet composition of the present invention can be used,e.g., for treatment of insomnia. In certain instances, after theintroduction of a chewable tablet into the mouth, the subject chews thechewable tablet as is normally done with any non-medicated type ofchewable tablet at approximately an average rate of about 10 to about 45chews per minute. In certain other instances, after the introduction ofa dissolving tablet into the mouth, the subject holds the tabletunderneath the tongue and either swallows while the tablet is dissolvingor swallows after the tablet has dissolved.

A typical dosage form of the zolpidem tablet of the present invention isdesigned to produce an average plasma concentration of at least fromabout 20 to about 300 nanograms of zolpidem per milliliter of plasma.For example, a 5 mg zolpidem tablet can be designed to produce a meanpeak plasma concentration within the range of from about 20 to about 100nanograms of zolpidem per milliliter of plasma within about 5 minutes toabout 2 hours. Similarly, a 10 mg zolpidem tablet can be designed toproduce a mean peak plasma concentration within the range of from about100 to about 300 nanograms of zolpidem per milliliter of plasma withinabout 5 minutes to about 2 hours.

The tablet compositions of the present invention provide a convenient,reliable, practical, and painless system for delivering zolpidem acrossthe oral mucosa. Notably, the tablet compositions are capable of rapidlydelivering zolpidem with low inter-subject variability in terms ofmaximum plasma concentration (C_(max)) and the time to reach the maximumplasma concentration (T_(max)) so that a therapeutically effectiveamount of zolpidem enters the bloodstream within about 30 minutes, 20minutes, 15 minutes, 10 minutes, 5 minutes, or even within about 1-2minutes after zolpidem is released from the carrier.

Example 4 Zolpidem Lozenge Compositions

This example illustrates the zolpidem lozenge compositions of thepresent invention.

Zolpidem can be formulated as a lozenge or candy composition asdescribed above. In these embodiments, the unit dose or serving of thelozenge comprises from about 0.1 to about 100 milligrams (mg) zolpidem(as measured in its tartrate salt form), preferably from about 1 toabout 50 mg, and more preferably from about 2 to about 25 mg. In otherembodiments, the unit dose comprises from about 2 to about 20 mgzolpidem, preferably from about 2 to about 15 mg, and more preferablyfrom about 2 to about 10 mg, e.g., about 2, 3, 4, 5, 6, 7, 8, 9, or 10mg. In particularly preferred embodiments, the unit dose comprises adose of zolpidem that is less than the dose typically used in commercialoral tablets, but possesses comparable or greater bioavailability andonset of therapeutic activity as well as lower inter-subject variabilityof drug absorption. In such embodiments, unit doses of from about 2 toabout 5 mg zolpidem are preferred, with unit doses of about 4 mgzolpidem being particularly preferred. Extra zolpidem, for example, upto from about 10% to about 25% by weight, can be added as “overage” oras the amount that may be expected to be “washed away” and not otherwisereleased or absorbed during lozenge dissolution and/or mastication.

In another embodiment, the unit dose or serving of the lozenge comprisesfrom about 0.81 to about 42 mg zolpidem in its base form, and morepreferably from about 1.64 to about 20.5 mg. In other embodiments, theunit dose comprises from about 1.64 to about 16.4 mg zolpidem in itsfree base form, preferably from about 1.64 to about 12.3 mg, and morepreferably from about 1.64 to about 8.2 mg, e.g., about 1.64, 2.46,3.28, 4.1, 4.92, 5.78, 6.56, 7.38, or 8.2 mg. In additional embodiments,the unit dose comprises a mixture of zolpidem in free base form and saltform (e.g., zolpidem tartrate).

Given in weight percentages, the zolpidem lozenge composition comprisesfrom about 0.001% to about 10.0% zolpidem (in whatever chosen form,measured as per its free base form), preferably from about 0.1% to about8.0%, more preferably from about 1.0% to about 7.0%, and still morepreferably from about 1.0% to about 5.5%. In some embodiments, about4.5% zolpidem is used. One skilled in the art understands that theforegoing percentages will vary depending upon the particular source ofzolpidem utilized, the amount of zolpidem desired in the finalformulation, as well as on the particular release rate of zolpidemdesired. The buffer system of the zolpidem lozenge composition providesfor a final salivary pH in excess of at least about 7.8, preferably atleast about 8.5, and more preferably at least about 9 (e.g., about9-11).

A zolpidem lozenge was made according to the formulation shown in Table4 and the following procedure. Three separate blends of silicon dioxidewith zolpidem, sodium carbonate, and sodium bicarbonate; Pharmaburst;and spearmint flavor, sucralose, magnesium stearate, and croscarmellosesodium were prepared. The three blends were screened separately andmixed to form a single blend. The single blend was then compressed intolozenges after testing for content uniformity. By using this procedure,the average particle size of the drug (i.e., zolpidem) in the lozenge isabout 20 microns, as compared to a typical average drug particle size offrom about 75 to about 100 microns. In addition, the average particlesize of the drug in the lozenge is less than or equal to the averageparticle size of the carrier ingredients (e.g., gum base, binders,etc.). The unit weight for each lozenge was 210 mg. The pH of thelozenge was about 9.8 and remained stable. These lozenges dissolvewithin about 2-3 minutes following sublingual administration.

TABLE 4 Zolpidem lozenge formulation. Material Unit Quantity (mg) BatchQuantity (g) Sodium Carbonate, NF 17.000 357.000 Sodium Bicarbonate(Effer 23.000 483.000 Soda) Zolpidem Tartrate, EP 10.000 210.000Pharmaburst B2 133.000 2793.000 Croscarmellose Sodium 10.000 210.000Natural & Artificial Spearmint 6.500 136.500 Flavor Sucralose, NF 1.50031.500 Silicon Dioxide, USP 5.500 115.500 Magnesium Stearate, NF 3.50073.500 The batch quantity formulation produces 21,000 unit doses.

The zolpidem lozenge composition of the present invention can be used,e.g., for treatment of insomnia. In certain instances, after theintroduction of a lozenge into the mouth, the subject holds the lozengeunderneath the tongue and either swallows while the lozenge isdissolving or swallows after the lozenge has dissolved. The lozengesdescribed herein have a very rapid rate of dissolution, and are capableof dissolving within about 2-3 minutes following sublingualadministration.

A typical dosage form of die Zolpidem lozenge of the present inventionis designed to produce an average plasma concentration of at least fromabout 20 to about 300 nanograms of zolpidem per milliliter of plasma.For example, a 5 mg zolpidem lozenge can be designed to produce a meanpeak plasma concentration within the range of from about 20 to about 100nanograms of zolpidem per milliliter of plasma within about 5 minutes toabout 2 hours. Similarly, a 10 mg zolpidem lozenge can be designed toproduce a mean peak plasma concentration within the range of from about100 to about 300 nanograms of zolpidem per milliliter of plasma withinabout 5 minutes to about 2 hours.

The lozenge compositions of the present invention provide a convenient,reliable, practical, and painless system for delivering zolpidem acrossthe oral mucosa. Notably, the lozenge compositions are capable of veryrapidly delivering zolpidem with low inter-subject variability in termsof maximum plasma concentration (C_(max)) and the time to reach themaximum plasma concentration (T_(max)) so that a therapeuticallyeffective amount of zolpidem enters the bloodstream within about 30minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, or even withinabout 1-2 minutes after zolpidem is released from the carrier.

Example 5 Dissolution Profiles for Zolpidem Tablet and LozengeCompositions

This example illustrates the mean dissolution profiles for a zolpidemquick-dissolving tablet made according to Table 3 and a zolpidem lozengemade according to Table 4.

The compositions tested were as follows:

1. Zolpidem quick-dissolving tablet (typically dissolves sublingually inabout 5 minutes).

2. Zolpidem lozenge (typically dissolves sublingually in about 2-3minutes).

The experimental conditions were as follows:

-   -   Method=USP    -   Apparatus=USP Apparatus II    -   Medium=Phosphate Buffer pH 6.8    -   Volume of the Medium=500 ml    -   Spindle Speed=25 rpm    -   Temperature=37° C.

Table 5 below shows the dissolution data and FIG. 2 shows the meandissolution profiles for a zolpidem quick-dissolving tablet and zolpidemlozenge of the present invention at 5, 10, 15, 20, and 30 minutes inphosphate buffered medium (pH 6.8).

TABLE 5 Dissolution data for the zolpidem quick- dissolving tablet andzolpidem lozenge. Time Quick-Dissolving Tablet Lozenge (Min.) (%Dissolved, RSD¹) (% Dissolved, RSD¹) 5 14.3, 17.7  32.4, 16.2 10 32.8,14.8 61.7, 8.6 15 50.1, 14.6 75.7, 4.9 20  63, 15.9 82.1, 4.6 30 85.2,7.9  88.6, 2.8 ¹RSD = Relative Standard Deviation

Example 6 Zolpidem Pharmacokinetic Studies

This example provides two studies illustrating the pharmacokineticprofile of the zolpidem tablets of the present invention as compared toa dose equivalent commercial oral tablet.

Zolpidem Sublingual Powdered Tablet vs. Ambien Oral Tablet:

To evaluate the pharmacokinetic profile of a sublingually administeredzolpidem formulation, a 10 mg zolpidem powdered tablet buffered at a pHof 9.8 with 23 mg sodium bicarbonate and 17 mg sodium carbonate(Formulation A) was determined in eight healthy subjects (5 male, 3female). Formulation A was administered under the subject's tongue andhad a very rapid dissolution rate, i.e., within about 1 to about 3minutes. The study performed was a fixed-sequence, open-labelpharmacokinetic study in which subjects swallowed saliva at a rate ofevery 2, 5, or 10 minutes over a 10 minute period of time (“swallowingtime”). For example, a 2 minute swallowing time refers to swallowingsaliva every 2 minutes over a 10 minute period (i.e., 5 blocks of 2minutes each); a 5 minute swallowing time refers to swallowing salivaevery 5 minutes over a 10 minute period (i.e., 2 blocks of 5 minuteseach); and a 10 minute swallowing time refers to swallowing saliva every10 minutes over a 10 minute period (i.e., 1 block of 10 minutes). Serumblood samples were collected over an 8 hour period and the plasma wasassayed for zolpidem levels, e.g., using high pressure liquidchromatography (HPLC)-tandem mass spectrometry (MS).

FIGS. 3-5 show the plasma concentration over time in each subject forFormulation A at swallowing times of 2, 5, and 10 minutes, respectively.Tables 6-8 below show the values for the pharmacokinetic parametersdetermined in each subject for Formulation A at swallowing times of 2,5, and 10 minutes, respectively.

TABLE 6 Pharmacokinetic parameters for Formulation A at a 2 minuteswallowing time. Subject T_(max) (min.) C_(max) (ng/ml) AUC₀₋₈ (ng ·hr/ml) 1 30 142 317 2 25 231 1096 3 180 211 776 4 90 141 430 5 50 182645 6 90 128 441 7 90 142 663 8 25 96 363 Median 70 (Range) (25-180)Mean 159 592 (CV %) (28%) (44%)

TABLE 7 Pharmacokinetic parameters for Formulation A at a 5 minuteswallowing time. Subject T_(max) (min.) C_(max) (ng/ml) AUC₀₋₈ (ng ·hr/ml) 1 30 134 350 2 25 252 1201 3 90 168 906 4 50 172 517 5 25 191 5206 90 146 490 7 120 185 805 8 40 77 464 Median 45 (Range) (25-120) Mean165 656 (CV %) (30%) (44%)

TABLE 8 Pharmacokinetic parameters for Formulation A at a 10 minuteswallowing time. Subject T_(max) (min.) C_(max) (ng/ml) AUC₀₋₈ (ng ·hr/ml) 1 390 137 364 2 25 241 913 3 120 183 824 4 90 120 508 5 50 196728 6 50 208 587 7 50 131 708 8 60 158 826 Median 55 (Range) (25-120)Mean 172 682 (CV %) (28%) (27%)

The pharmacokinetic results obtained for Formulation A were thencompared to pharmacokinetic data obtained from the package insert andthe literature for a dose equivalent Ambien® oral tablet formulation(Formulation B). FIG. 6 shows the mean plasma concentration over timefor Formulation A (zolpidem sublingual powdered tablet) at the 3different swallowing times and for Formulation B (peroral (PO) Ambien®),which was obtained from the literature (Greenblatt et al., Clin.Pharmacol. Ther., 64:553-561 (1998); Greenblatt et al., Clin. Pharmacol.Ther., 64:661-671 (1998)). Table 9 below shows the mean values for thepharmacokinetic parameters determined for Formulation A at the 3different swallowing times and those for Formulation B from theliterature (Greenblatt et al., Clin. Pharmacol. Ther., 64:553-561(1998)).

TABLE 9 Pharmacokinetic parameters for Formulation A and Formulation B.Formulation T_(max) (min.) C_(max) (ng/ml) AUC (ng · hr/ml) FormulationA 70 159 592 (2 min. swallowing (25-180) (28%) (44%) time) Formulation A45 165 656 (5 min. swallowing (25-120) (30%) (44%) time) Formulation A55 172 682 (10 min. swallowing (25-120) (24%) (27%) time) Formulation A55 166 644 (Cumulative) (25-180) (25%) (37%) Formulation B 102  125 408(84-120) (12%) (12%) Values represent the mean. The numbers inparentheses for T_(max) represent the minimum and maximum values,respectively. The numbers in parentheses for C_(max) and AUC representthe coefficient of variation percent (CV %).

This study demonstrates that delivery of zolpidem across the oral mucosaproduced mean plasma zolpidem concentrations that were from about 45% toabout 67% greater than those observed for the commercial oral tabletduring the 8 hour period following administration. In addition, peakplasma zolpidem concentrations were achieved within about 45 to about 70minutes following sublingual administration, while peak plasma zolpidemconcentrations were not achieved until 96 minutes (Ambien® packageinsert) or 102 minutes (Greenblatt et al., Clin. Pharmacol. Ther.,64:553-561 (1998)) following commercial oral tablet administration. Assuch, the present study shows that zolpidem from the powdered sublingualtablet is rapidly absorbed and has substantially better bioavailabilitythan the commercial oral tablet. The present study also shows that theimprovement in bioavailability is independent of the swallowing time.

FIG. 7 shows the mean plasma concentration over time for Formulation Aat swallowing times of 2 and 5 minutes using the data from all 8subjects and the mean plasma concentration over time for Formulation Aat swallowing times of 2 and 5 minutes excluding the data from subjects3, 6, and 7, who apparently swallowed earlier than their scheduledswallowing time. Table 10 below shows the mean values for thepharmacokinetic parameters determined for Formulation A using the datafrom all 8 subjects or excluding the data from subjects 3, 6, and 7.When subjects who apparently did not comply with the study protocol wereexcluded from the analysis, peak plasma zolpidem concentrations for theremaining subjects were achieved within about 30 minutes rather thanfrom about 45 to about 70 minutes following sublingual administration.

TABLE 10 Pharmacokinetic parameters for Formulation A with all subjectsor excluding those who swallowed early. Swallowing Time T_(max) (min.)C_(max) (ng/ml) AUC (ng · hr/ml) 2 minutes 70 159 592 (all subjects)(25-180) (28%) (44%) 2 minutes 30 159 570 (excluding subjects 3, 6,(25-90)  (31%) (44%) and 7) 5 minutes 45 165 656 (all subjects) (25-120)(30%) (56%) 5 minutes 30 165 609 (excluding subjects 3, 6, (25-50) (40%) (55%) and 7) Values represent the mean. The numbers in parenthesesfor T_(max) represent the minimum and maximum values, respectively. Thenumbers in parentheses for C_(max) and AUC represent the coefficient ofvariation percent (CV %).

FIG. 8 is an expanded view of the first 90 minutes shown in FIG. 6. Inparticular, FIG. 8 illustrates the estimated time for the onset of sleepin subjects taking Formulation A (left dotted line) compared to the timefor the onset of sleep in subjects taking Formulation B (right dottedline). The mean plasma zolpidem concentration effective for inducingsleep onset is shown by the horizontal line in FIG. 8. Table 11 belowshows the reported time for the onset of sleep during the daytime ineach subject taking Formulation A at the 3 different swallowing times.

TABLE 11 Reported daytime sleep onset times for Formulation A. 2 min.swallowing 5 min. swallowing 10 min. swallowing Subject time (min.) time(min.) time (min.) 1 10 16 18 2 12 9 14 3 7 7 18 4 49 19 8 5 5 19 24 630 19 18 7 25 23 15 8 13 24 14 Median 12.5 19 16.5

This study demonstrates that the onset of sleep for subjects taking thezolpidem powdered sublingual tablet is substantially faster than thatachieved with the commercial oral tablet. In fact, the onset of sleepfor subjects taking the sublingual tablets of the present invention canbe as early as within about 12.5 minutes following administration, whichis more than 3 times faster than the onset of sleep for subjects takingthe commercial oral tablet. One skilled in the art will appreciate thatthe onset of sleep observed during the daytime corresponds to the onsetof sleep at night.

Furthermore, the pharmacokinetic profiles for sublingually administeredzolpidem provide a softer and longer-lasting peak of zolpidem (see, FIG.6), and thus resemble a pharmacokinetic profile for intravenouslyadministered zolpidem. As a result, this infusion-like pharmacokineticprofile is equivalent to or even superior to the commercial oral tabletin reducing the time to onset of therapeutic activity, maintaining sleep(e.g., total sleep time, number of awakenings), enhancing sleep quality,eliminating the effect of food, and reducing any morning-after residualeffects.

Zolpidem Slow-Dissolving and Quick-Dissolving Sublingual Tablets vs.Ambien Oral Tablet:

To further evaluate the pharmacokinetic profile of a sublinguallyadministered zolpidem formulation, a 10 mg zolpidem slow-dissolvingtablet made according to Table 2 (Formulation C) and a 10 mg zolpidemquick-dissolving tablet made according to Table 3 (Formulation D) wascompared to a dose equivalent Ambier® oral tablet formulation(Formulation B) in eight healthy subjects. Formulation C (SL Tablet) wasadministered under the subject's tongue and had a slow dissolution rate,i.e., within about 10 minutes. Formulation D (FS Tablet) wasadministered under the subject's tongue and had a fast dissolution rate,i.e., within about 5 minutes. Formulation B (PO Ambien) was administeredperorally with 180 ml of water. The study performed was a three-waycrossover, fixed-sequence pharmacokinetic study in which subjectsswallowed saliva at a rate of every 2 or 5 minutes over a 10 minuteperiod of time (“swallowing time”) for Formulations C and D. Serum bloodsamples were collected over a 12 hour period and the plasma was assayedfor zolpidem levels, e.g., using high pressure liquid chromatography(HPLC)-tandem mass spectrometry (MS).

FIG. 9 shows the mean plasma concentration over time for Formulation C(SL Tablet) at swallowing times of 2 and 5 minutes and for Formulation B(PO Ambien). Likewise, FIG. 10 shows the mean plasma concentration overtime for Formulation D (FS Tablet) at swallowing times of 2 and 5minutes and for Formulation B (PO Ambien). This study demonstrates thatdelivery of zolpidem across the oral mucosa produced peak plasmazolpidem concentrations at a substantially earlier period in time and ata substantially higher level following sublingual administration thanobserved for the commercial oral tablet administration. As such, thepresent study shows that zolpidem from both dissolving tablets israpidly absorbed and has substantially better bioavailability than thecommercial oral tablet. Furthermore, the onset of sleep for subjectstaking either zolpidem dissolving tablet is substantially faster thanthat achieved with the commercial oral tablet. The present study alsoshows that the improvement in bioavailability is independent of theswallowing time and the formulation of the dissolving tablet.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Although the foregoing invention has beendescribed in some detail by way of illustration and example for purposesof clarity of understanding, it will be readily apparent to those ofordinary skill in the art in light of the teachings of this inventionthat certain changes and modifications may be made thereto withoutdeparting from the spirit or scope of the appended claims.

What is claimed is:
 1. A solid composition for delivery of a hypnoticagent across the oral mucosa, said composition comprising: (a) ahypnotic agent selected from the group consisting of an imidazopyridine,a dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceuticallyacceptable salt thereof; (b) a carrier that provides complete buccal orsublingual disintegration in about 5 minutes or less followingadministration to the mouth; and (c) a binary buffer system comprising acarbonate salt and a bicarbonate salt, wherein said binary buffer systemraises the pH of saliva to a pH greater than about 7.8, irrespective ofthe starting pH of saliva.
 2. The composition of claim 1, wherein saidbinary buffer system raises the pH of saliva to a pH greater than about8.5, irrespective of the starting pH of saliva.
 3. The composition ofclaim 1, wherein said binary buffer system raises the pH of saliva to apH greater than about 9, irrespective of the starting pH of saliva. 4.The composition of claim 1, wherein said carrier provides completebuccal or sublingual disintegration in about 2 minutes or less followingadministration.
 5. The composition of claim 1, wherein said carriercomprises at least one binder and at least one disintegrating agent insuch relative proportion to provide a buccal or sublingualdisintegration time of about 5 minutes or less following administration.6. The composition of claim 5, wherein the ratio of said binder to saiddisintegrating agent is from about 0.26 to about 0.79.
 7. Thecomposition of claim 5, wherein said binder is selected from the groupconsisting of a sugar, a sugar alcohol, and combinations thereof.
 8. Thecomposition of claim 7, wherein said sugar alcohol is selected from thegroup consisting of mannitol, sorbitol, xylitol, and combinationsthereof.
 9. The composition of claim 1, wherein said imidazopyridine isselected from the group consisting of zolpidem and alpidem.
 10. Thecomposition of claim 1, wherein said dihydropyrrolopyrazine is zopeclon.11. The composition of claim 1, wherein said pyrazolopyrimidine isselected from the group consisting of zaleplon and indiplon.
 12. Thecomposition of claim 1, wherein said carbonate salt is selected from thegroup consisting of sodium carbonate and potassium carbonate.
 13. Thecomposition of claim 1, wherein said bicarbonate salt is selected fromthe group consisting of sodium bicarbonate and potassium bicarbonate.14. The composition of claim 1, wherein said binary buffer systemcomprises sodium carbonate and sodium bicarbonate.
 15. The compositionof claim 1, wherein said composition further comprises a sweeteningagent, a flavoring agent, a protecting agent, a plasticizer, a wax, anelastomeric solvent, a filler material, a preservative, a lubricatingagent, a wetting agent, an emulsifying agent, a solubilizing agent, asuspending agent, a coloring agent, a disintegrating agent, orcombinations thereof.
 16. The composition of claim 1, wherein saidcomposition is a dosage form selected from the group consisting of alozenge, a chewing gum, a chewable tablet, and a dissolving tablet. 1.The composition of claim 1, wherein said oral mucosa is selected fromthe group consisting of the sublingual mucosa, the buccal mucosa, and acombination thereof.
 18. The composition of claim 1, wherein saidhypnotic agent is zolpidem and said binary buffer system comprisessodium carbonate and sodium bicarbonate.
 19. The composition of claim18, wherein said zolpidem is selected from the group consisting of apharmaceutically acceptable salt thereof, a free base thereof, andmixtures thereof.
 20. A solid composition for delivery of a hypnoticagent across the oral mucosa, said composition comprising: (a) atherapeutically effective amount of zolpidem; (b) a carrier thatprovides complete buccal or sublingual disintegration in about 5 minutesor less following administration to the mouth; and (c) a binary buffersystem comprising a carbonate salt and a bicarbonate salt, wherein saidbinary buffer system raises the pH of saliva to a pH greater than about7.8, irrespective of the starting pH of saliva